Aryl methyl benzoquinazolinone m1 receptor positive allosteric modulators

ABSTRACT

The present invention is directed to benzoquinazilinone compounds of formula (I) 
     
       
         
         
             
             
         
       
     
     which are M1 receptor positive allosteric modulators and that are useful in the treatment of diseases in which the M1 receptor is involved, such as Alzheimer&#39;s disease, schizophrenia, pain or sleep disorders. The invention is also directed to pharmaceutical compositions comprising the compounds, and to the use of the compounds and compositions in the treatment of diseases mediated by the M1 receptor.

FIELD OF THE INVENTION

The invention is directed to a class of aryl methyl benzoquinazolinonecompounds, their sails, pharmaceutical compositions comprising them andtheir use in therapy of the human body. In particular, the invention isdirected to a class of benzoquinazolinone compounds which are muscarinicM1 receptor positive allosteric modulators, and hence are useful in thetreatment of Alzheimer's Disease and other diseases mediated by themuscarinic M1 receptor.

BACKGROUND OF THE INVENTION

Alzheimer's Disease is a common neurodegenerative disease affecting theelderly, resulting in progressive memory impairment, loss of languageand visuospatial skills, and behavior deficits. Characteristics of thedisease include degeneration of cholinergic neurons in the cerebralcortex, hippocampus, basal forebrain, and other regions of the brain,neurofibrillary tangles, and accumulation of the amyloid β peptide (Aβ).Aβ is a 39-43 amino acid produced in the brain by processing of thebeta-amyloid precursor protein (APP) by the beta-amyloid proteincleaving enzyme (“beta secretase” or “BACE”) and gamma-secretase. Theprocessing leads to accumulation of Aβ in the brain.

Cholinergic neurotransmission involves the binding of acetylcholineeither to the nicotinic acetylcholine receptor (nAChR) or to themuscarinic acetylcholine receptor (mAChR). It has been hypothesized thatcholinergic hypofunction contributes to the cognitive deficits ofpatients suffering from Alzheimer's Disease. Consequently, acetylcholinesterase inhibitors, which inhibit acetylcholine hydrolysis, havebeen approved in the United States for use in the treatment of thecognitive impairments of Alzheimer's Disease patients. While acetylcholinesterase inhibitors have provided some cognitive enhancement inAlzheimer's Disease patients, the therapy has not been shown to changethe underlying disease pathology.

A second potential pharmacotherapeutic target to counteract cholinergichypofunction is the activation of muscarinic receptors. Muscarinicreceptors are prevalent throughout the body. Five distinct muscarinicreceptors (M1-M5) have been identified in mammals. In the centralnervous system, muscarinic receptors are involved in cognitive,behavior, sensory, motor and autonomic functions. The muscarinic M1receptor, which is prevalent in the cerebral cortex, hippocampus andstriatum, has been found to have a major role in cognitive processingand is believed to have a role in the pathophysiology of Alzheimer'sDisease. See Eglen et al, TRENDS in Pharmacological Sciences. 2001,22:8, 409-414. In addition, unlike acetyl cholinesterase inhibitors,which are known to provide only symptomatic treatment, M1 agonists alsohave the potential to treat the underlying disease mechanism ofAlzheimer's Disease. The cholinergic hypothesis of Alzheimer's Diseaseis linked to both β-amyloid and hyperphosphorylated tau protein.Formation of β-amyloid may impair the coupling of the muscarinicreceptor with G-proteins. Stimulation of the M1 muscarinic receptor hasbeen shown to increase formation of the neuroprotective αAPPs fragment,thereby preventing the formation of the Aβ peptide. Thus, M1 agonistsmay alter APP processing and enhance αAPPs secretion. See Fisher, Jpn JPharmacol, 2000, 84:101-112.

However, M1 ligands which have been developed and studied forAlzheimer's Disease have produced side effects common to othermuscarinic receptor ligands, such as sweating, nausea and diarrhea. SeeSpalding et al. Mol Pharmacol, 2002, 61:6, 1297-1302.

The muscarinic receptors are known to contain one or more allostericsites, which may alter the affinity with which muscarinic ligands bindto the primary binding or orthosteric sites. See, e.g., S. Lazareno etal, Mol Pharmacol, 2002, 62:6, 1491-1505; S. Lazareno et al, MolPharmacol, 2000, 58, 194-207.

Thus the compounds of the invention, which are muscarinic M1 receptorpositive allosteric modulators, are believed to be useful in thetreatment of Alzheimer's Disease and other diseases mediated by themuscarinic M1 receptor.

SUMMARY OF THE INVENTION

The present invention is directed to novel aryl methylbenzoquinazolinone compounds of generic formula (I)

or a pharmaceutically acceptable salt thereof, which is useful as an M1receptor positive allosteric modulator.

The invention is further directed to methods of treating a patient(preferably a human) far diseases or disorders in which the M1 receptoris involved, such as Alzheimer's disease, cognitive impairment,schizophrenia, pain disorders and sleep disorders, by administering tothe patient a therapeutically effective amount of a compound of generalformula (I), or a pharmaceutically acceptable salt thereof. Theinvention is also directed to pharmaceutical compositions which includean effective amount of a compound of formula (I), or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable carrier, andthe use of the compounds and pharmaceutical compositions of theinvention in the treatment of such diseases.

DETAILED DESCRIPTION OF THE INVENTION

In one embodiment, the invention is directed to aryl methylbenzoquinazolinone compounds of general formula (I)

-   and pharmaceutically acceptable salts thereof, wherein-   X, Y and Z are each CH and Q is C, or one of X, Y, Q and Z is N and    the others are CH or C, or X and Y are CH and Q, R¹ and Z are linked    together to form a naphthyl group;-   R¹ is selected from the group consisting of

(1) hydrogen,

(2) aryl,

(3) a heteroaryl group which is a cyclic or polycyclic group, havingfrom five to twelve ring atoms, said ring atoms selected from C, O, N orS, at least one of which is O, N or S,

(4) halogen,

(5) —CN.

(6) —O—C₁₋₆alkyl,

(7) —C₁₋₆ alkyl,

(8) —C₂₋₆ alkenyl

(9) —S(═O)_(n)—R⁴,

(10) —NR⁵A_(R)5B,

wherein said aryl, heteroaryl, alkyl and alkenyl moiety is optionallysubstituted with one or more

-   -   (a) halogen,    -   (b) hydroxy,    -   (c) —O—C₁₋₆ alkyl,    -   (d) —C₁₋₆ alkyl,    -   (e) —C(═O)—(O)_(m)—R⁶,    -   (f) —N(R^(5A)R^(5B)),    -   (g) —S(═O)_(n)—R⁸, or    -   (h) oxo,

provided that when Q is N then R¹ is absent:

-   R² is selected from the group consisting of

(1) hydrogen,

(2) aryl,

(3) a heteroaryl group which is a cyclic or polycyclic group, havingfrom five to twelve ring atoms, said ring atoms selected from C, O, N orS, at least one of which is O, N or S,

(4) a heterocyclic group, which is a non-aromatic cyclic or polycyclicgroup having from five to twelve ring atoms selected from C, O, N or S,at least one of which is O, N or S,

(5) —O—C₁₋₆ alkyl,

(6) —C₁₋₆ alkyl

(7) —C₂₋₆ alkenyl,

(8) —S(═O)_(n)—R⁴,

(9) —C₃₋₈ cycloalkyl,

(10) —C₅₋₈ cycloalkenyl,

(11) —NR^(5A)R^(5B),

-   -   wherein said aryl, heteroaryl, heterocyclyl, alkyl, alkenyl,        cycloalkyl and cycloalkenyl moiety is optionally substituted        with one or more    -   (a) halogen,    -   (b) hydroxy,    -   (c) —O—C₁₋₆ alkyl,    -   (d) —C₁₋₆ alkyl,    -   (e) —S—(═O)_(n)—R⁸,    -   (f) —C₂₋₆ alkenyl,    -   (g) —CN,    -   (h) —C(═O)—(O)_(m)—R⁶,    -   (i) —NR^(5A)R^(5B),    -   (j) oxo,    -   (k) aryl,    -   (l) a heteroaryl group which is a cyclic or polycyclic group,        having from five to twelve ring atoms, said ring atoms selected        from C, O, N or S, at least one of which is O, N or S,    -   (m) a heterocyclic group, which is a non-aromatic cyclic or        polycyclic group having from five to twelve ring atoms selected        from C, O, N or S, at least one of which is O, N or S    -   (n) —OC═(O)—R⁶,    -   wherein the alkyl, alkenyl, aryl, heteroaryl or heterocyclic        moiety is optionally substituted with one or more        -   (i) halogen,        -   (ii) —C₁₋₆ alkyl, or        -   (iii) —OC₁₋₆ alkyl;

-   R³ is selected from the group consisting of

(1) hydrogen.

(2) —C₁₋₆ alkyl, and

(3) —S(O)_(n)—R⁴,

wherein said R³ alkyl moiety is optionally substituted with one or more

-   -   (a) halogen,    -   (b) cyano, and    -   (c) —O—C₁₋₆ alkyl, wherein said alkyl is optionally substituted        with one or more halo;

-   R⁴, R⁶ and R⁸ are independently selected from the group consisting    of

(1) hydrogen,

(2) —C₁₋₆ alkyl, and

(3) —(CH₂)_(n)-aryl,

wherein said R⁴, R⁶ and R⁸ alkyl or aryl moiety is optionallysubstituted with one or more

-   -   (a) halogen,    -   (b) cyano, and    -   (c) —O—C₁₋₆ alkyl, wherein said alkyl is optionally substituted        with one or more halogen;

-   R^(5A) and R^(5B) are selected from the group consisting of

(1) hydrogen,

(2) —C₁₋₆ alkyl,

(3) —C₃₋₆ cycloalkyl,

(4) —C(═O)—O—R⁶,

(5) —S(O)₂—R⁶,

or R^(5A) and R^(5B) are linked together with the nitrogen to which theyare both attached to form a 2-6 membered carbocyclic ring, wherein oneor two of the ring carbon atoms is optionally replaced by a nitrogen,oxygen or sulfur;

-   m is 0 or 1; and-   n is 0,1 or 2.

In particular embodiments, Q is C, X and Y each CH and Z is N.

In other embodiments, X, Y, Z are each CH, and Q is C.

In other embodiments, X and Z are each CH, Q is C and Y is N.

In other embodiments, X and Y are CH, and Q, R¹ and Z are linkedtogether to form a naphthyl group.

In particular embodiments of the compounds of formula (I), R¹ isselected from the group

consisting of

(1) halogen (suitably fluoro or chloro),

(2) —CN,

(3) —O—C₁₋₆ alkyl, or

(4) —C₁₋₆ alkyl,

wherein said alkyl is optionally substituted with one or more

-   -   (a) halogen,    -   (b) hydroxy,    -   (c) —O—C₁₋₆ alkyl,    -   (d) —C₁₋₆ alkyl,    -   (e) —C(═O)—(O)_(m)—R⁶,    -   (f) —NR^(5A)R^(5B), or    -   (g) oxo.    -   In other embodiments of the compounds of formula (I). R¹ is        selected from the group consisting of

(1)aryl, or

(2) heteroaryl, as described above,

wherein said aryl or heteroaryl is optionally substituted as describedabove. A suitable R¹ aryl group is phenyl. Suitable R¹ heteroaryl groupsinclude pyridyl, pyrazolyl, pyrimidinyl, and imidazolyl. In certainembodiments, the R¹ aryl or heteroaryl moiety is optionally substitutedwith one or more

-   -   (a) halogen,    -   (b) hydroxy,    -   (c) —O—C₁₋₆ alkyl    -   (d) —C₁₋₆ alkyl, or    -   (e) —S—(═O)_(n)—R⁸.

Exemplary R¹ groups include hydrogen, methyl, isopropyl,1-hydroxy-1-methylethyl, hydroxymethyl, cyano, methylsulfonyl, oxo,chloro, methoxy, phenyl, 1-methyl-1H-pyrazol-4-yl, 1H-pyrazol-1-yl,1-isobutyl-1H-pyrazol-4-yl, 1H-pyrazol-4-yl, 3-pyridyl,6-fluoro-pyridyl-3-yl, 6-methoxy-pyridyl-3-yl, 6-methyl-pyridyl-3-yl,5-fluoro-pyridyl-3-yl, 5-methyl-pyridyl-3-yl, 5-methyl-pyridyl-3-yl,5-chloro-pyridyl-3-yl, 5-methoxy-pyridyl-3-yl, 1-methyl-1H-imidazolyland dimethylamino.

In particular, embodiments of the compounds of formula (I), R² is —C₃₋₈cycloalkyl, such as cyclopentyl or cyclohexyl, optionally substituted asdescribed above. Suitably, the —C₃₋₈ cycloalkyl group is substitutedwith one or more

(a) hydroxy,

(b) —O—C₁₋₆ alkyl, or

(c) oxo.

In other embodiments, R² is selected from the group consisting of

(1) aryl, or

(2) heteroaryl (as described above), or

(3) —C₁₋₆ alkyl, wherein said aryl, heteroaryl or alkyl is optionallysubstituted as described above. Suitably, the R² aryl group is phenyl.Suitable R² heteroaryl groups include pyridyl, pyrazolyl, imidazolyl,indazolyl, triazoryl and azaindolizinyl. In some embodiments, the aryl,heteroaryl or alkyl group is substituted with one or more

-   -   (a) halogen,    -   (b) hydroxy,    -   (c) —O—C₁₋₆ alkyl,    -   (d) —C₁₋₆ alkyl,    -   (e) —CN,    -   (f) —C(═O)—(O)_(m)—R⁶,    -   (g) —NR^(5A)R^(5B),    -   (h) oxo,    -   (k) aryl,(h) oxo,    -   (i) aryl, and    -   (j) heteroaryl.

Exemplary R² groups include 2-hydroxylcyclohexyl (suitably 1S,2S-2-hydroxycyclohexyl), 2-methoxycyclohexyl,2-methyl-2-hydroxy-cyclohexyl, 2-aminocyclohexyl,2-methylaminocyclohexyl, 2-acetylammocyclohexyl,2-dimethylaminocyclohexyl, 2-oxycyclohexyl, 2-acetylcyclohexyl,2-acetoxycyclohexyl, 2-mesylaminocyclohexyl, 2-acetamide cyclohexyl,2-hydroxycyclopentyl, 5-methyl-1H-pyrazol-3-yl, 1H-pyrazol-3-yl,4-(2-thienyl)-1H-pyrazol-3-yl, 4-(2-pyridyl)-1H-pyrazol-3-yl,4-cyano-2-methyl-1H-pyrazol-3-yl,4-carboxyethyl-2-methyl-1H-pyrazol-3-yl, 3-fluorophenyl-1H-pyrazol-3-yl,(1-ethyl-piperidin-4-yl)-1H-pyrazol-4-yl, 3-pyridyl, 4-pyridyl, phenyl,2-fluorophenyl, 2-methylphenyl, hydrogen, isobutyl, 2-hydroxyethyl,2-cyanoethyl, methyl, allyl, tetrahydropyran, cycloalkenyl,1,2,4-triazol-3-yl, 5-furan-2-yl-1,2,4-triazol-3-yl,5-pyridin-2-yl-1,2,4-triazol-3-yl, 1-phenyl-1,2,4-triazol-3-yl,1-methyl-1,2,3-triazol-4-yl, 2-methyl-1,2,3-triazol-4-yl, indazol-3-yl,azaindolizine and tetrahydropyrazopyrimidine.

In particular embodiments of the compounds of formula (II), R³ ishydrogen.

In alternative embodiments of the compounds of formula (I), R³ isselected from —C₁₋₆ alkyl (typically methyl or ethyl), and —S(O)_(n)—R⁴,wherein R⁴ is typically—C₁₋₆ alkyl, such as methyl or ethyl.

Exemplary R³ groups include hydrogen, methyl, and methylthio.

In one embodiment, the invention is directed to methods of treating apatient (preferably a human) for diseases in which the M1 receptor isinvolved, such as Alzheimer's Disease, cognitive impairment,schizophrenia, pain disorders and sleep disorders, by administering tothe patient a therapeutically effective amount of a compound of generalformula (I).

The invention is also directed to the use of a compound of formula (I)for treating diseases or disorders in which the M1 receptor is involved,such as Alzheimer's disease, cognitive impairment, schizophrenia paindisorders and sleep disorders.

The invention is also directed to medicaments or pharmaceuticalcompositions for treating diseases or disorders in which the M1 receptoris involved, such as Alzheimer's disease, cognitive impairment,schizophrenia, pain disorders and sleep disorders, which comprise acompound of formula (I), or a pharmaceutically acceptable salt thereof,and a pharmaceutically acceptable carrier.

The invention is further directed to a method for the manufacture of amedicament or a composition for treating diseases or disorders in whichthe M1 receptor is involved, such as Alzheimer's disease, cognitiveimpairment, schizophrenia, pain disorders and sleep disorders,comprising combining a compound of formula (I) with one or morepharmaceutically acceptable carriers.

Within the genus of compounds of formula (I), there is a sub-genus ofcompounds of formula (II):

and pharmaceutically acceptable salts thereof, wherein

-   R² and R³ are as described above, and R⁷ is selected from the group    consisting of

(1) hydrogen,

(2) aryl,

(3) heteroaryl (as described above),

(4) halogen,

(5) —CN,

(6) —O—C₁₋₆ alkyl,

(7) —C₁₋₆ alkyl,

(8) —C₂₋₆ alkenyl

(9) —S(═O)_(n)—R⁴, and

(10) —NR^(5A)R^(5B),

wherein said aryl, heteroaryl, alkyl and alkenyl moiety is optionallysubstituted with one or more

-   -   (a) halogen,    -   (b) hydroxy,    -   (c) —O—C₁₋₆ alkyl,    -   (d) —C₁₋₆ alkyl,    -   (e) —C(═O)—(O)_(m)—R⁶,    -   (f) —NR^(5A)R^(5B),    -   (g) —S(═O)_(n)—R⁸, and    -   (h) oxo,

In particular embodiments of the compounds of formula (II), R⁷ isselected from the group consisting of

(1)halogen (suitably fluoro or chloro),

(2) —CN,

(3—C₁₋₆ alkyl, or

(4) —C₁₋₆ alkyl,

wherein said alkyl is optionally substituted with one or more

-   -   (a) halogen,    -   (b) hydroxy,    -   (c) —O—C₁₋₆ alkyl,    -   (d) —C₁₋₆ alkyl,    -   (e) —C(═O)—(O)_(m)—R⁶,    -   (f) —NR^(5A)R^(5B),    -   (g) oxo,

In other embodiments of the compounds of formula (II), R⁷ is selectedfrom the group consisting of

(1) aryl, or

(2) heteroaryl (as described above).

wherein said aryl or heteroaryl is optionally substituted as describedabove. A suitable R₇ aryl group is phenyl. Suitable R⁷ heteroaryl groupsinclude pyridyl, pyrazolyl, pyrimidinyl, and imidaxolyl. In certainembodiments, the R⁷ aryl or heteroaryl is substituted with one or more

-   -   (a) halogen,    -   (b) hydroxy,    -   (c) —O—C₁₋₆ alkyl, or    -   (d) —C₁₋₆ alkyl,

Exemplary R⁷ groups for compounds of formula (II) groups include methyl1-methyl-1H-pyrazol-4-yl, 1H-pyrazol-1-yl, cyano, methysulfonyl, chloro,isopropyl, 1-hydroxy-1-methylethyl, hydroxymethyl, oxo, 3-pyridyl,1-methyl-1H-imidazolyl, dimethylamino, cyano,1-isobutyl-1H-pyrazol-4-yl, 1H-pyrazol-4-yl, 6-fluoro-pyridyl-3-yl,6-methoxy-pyridyl-3-yl, 6-methyl-pyridyl-3-yl, 5-fluoro-pyridyl-3-yl,5-methyl-pyridyl-3-yl, 5-methyl-pyridyl-3-yl, 5-chloro-pyridyl-3-yl, and5-methoxy-pyridyl-3-yl.

In another sub- genus within the genus of compounds of formula (I),there are compounds of formula (III):

and, pharmaceutically acceptable salts thereof, wherein

-   R² and R³ are as described above, and R⁷ is selected from the group    consisting of

(1) hydrogen,

(2) aryl,

(3) heteroaryl (as described above),

(4) halogen,

(5) —CN,

(6) —O—C₁₋₆ alkyl,

(7) —C₁₋₆ alkyl,

(8) —C₂₋₆ alkenyl

(9) —S(═O)_(n)—R⁴, and

(10) —NR^(5A)R^(5B),

wherein said aryl, heteroaryl, alkyl and alkenyl moiety is optionallysubstituted with one or more

-   -   (a) halogen,    -   (b) hydroxy,    -   (c) —O—C₁₋₆ alkyl,    -   (d) —C₁₋₆ alkyl,    -   (e) —C(═O)—(O)_(m)—R⁶,    -   (f) —NR^(5A)R^(5B),    -   (g) —S(═O)_(n)—R⁸, and    -   (h) oxo,

In particular embodiments of the compounds of formula (III), R⁷ isselected from the group consisting of

(1) halogen (suitably fluoro or chloro),

(2) —CN.

(3) —O—C₁₋₆ alkyl, or

(4) —C₁₋₆ alkyl,

wherein said alkyl is optionally substituted as described above.

In other embodiments of the compounds of formula (III), R⁷ is selectedfrom the group consisting of

(1) aryl, or

(2) heteroaryl (as described above),

wherein said aryl or heteroaryl is optionally substituted as describedabove. A suitable R⁷ aryl group is phenyl. Suitable R⁷ heteroaryl groupsinclude pyridyl, pyrazolyl, pyrimidinyl, and imidazolyl. In certainembodiments, the R⁷ aryl or heteroaryl is substituted with one or more

-   -   (a) halogen,    -   (b) hydroxy,    -   (c) —O—C₁₋₆ alkyl, or    -   (d) —C₁₋₆ alkyl.

Exemplary R₇ groups for compounds of formula (III) include methoxy,chloro, 1-methyl-1H-pyrazol-4-yl, 3-pyridyl, phenyl, 1H-pyrazol-1-yl andhydrogen.

In another sub-genus within the genus of compounds of formula (I), thereare compounds of formula IV):

and pharmaceutically acceptable salts thereof, wherein X, Y, Z, R¹ andR³ are as described above. In particular embodiments, compound offormula (IV) have a particular relative stereochemistry. In thisembodiment, the bonds between the benzoquinazoline nitrogen and the1-carbon on the cyclohexyl ring, and the bond between the hydroxy andthe 2-carbon on the cyclohexyl ring, are trans (i.e., are in oppositestereochemical configurations), as shown below in formula (IVA):

Compounds of formula (IVA) have either a (1S, 2S) or (1R, 2R) absolutestereochemistry.

In particular embodiments of compounds of formulae (IV) and (IVA), X andY are each CH and Z is N.

In other embodiments of compounds of formulae (IV) and (IVA), X, Y and Zare each CH.

In other embodiments of compounds of formulae (IV) and (IVA), X and Zare each CH, and Y is N. In other embodiments of compounds of formulae(IV) and (IVA), X and Y are each CH and Q, R¹ and Z are linked togetherto form a naphthyl group.

In particular embodiments of the compounds of formulae (IV) and (IVA),R¹ is selected from the group consisting of

(1) halogen (suitably fluoro or chloro),

(2) —CN,

(3) —O—C₁₋₆ alkyl, or

(4) —C₁₋₆ alkyl,

wherein said alkyl is optionally substituted as described above.Suitably, the R¹ alkyl moiety is optionally substituted with one or more

-   -   (a) halogen,    -   (b) hydroxy,    -   (c) —O—C₁₋₆ alkyl, or    -   (d) —C₁₋₆ alkyl.    -   (e) —C(═O)—(O)_(m)—R⁶,    -   (f) —NR^(5A)R^(5B),    -   (g) —S(═O)_(n)—R⁸, and    -   (h) oxo.

In other embodiments of the compounds of formulae (IV) and (IVA). R¹ isselected from the group consisting of

(1) aryl, or

(2) heteroaryl,

wherein said aryl or heteroaryl is optionally substituted as describedabove. A suitable R¹ aryl group is phenyl. Suitable R¹ heteroaryl groupsinclude pyridyl, pyrazolyl, pyrimidinyl, and imidazolyl. In certainembodiments, the R¹ aryl or heteroaryl moiety is substituted with one ormore

-   -   (a) halogen.    -   (b) hydroxy,    -   (c) —O—C₁₋₆ alkyl, or    -   (d) —C₁₋₆ alkyl.

Specific embodiments of formula (I) are described herein as Examples1-131, such as

-   rac-3-[trans-2-hydroxyclohexyl]-6-[(6-methylpyridin-3-yl)methyl]benzo[h]quinazolin-4(3H)-one    (Example 1);-   3-[(1S,2S)-2-hydroxycyclohexyl]-6-[(6-methylpyridin-3-yl)methyl]benzo[h]quinazolin-4(3H)-one    (Example 2);-   6-(4-methoxybenzyl)-3-(5-methyl)-1H-pyrazol-3-yl)benzo[h]quinazolin-4(3H)-one    (Example 3);-   6-(4-methoxybenzyl)-3-pyridin-3-ylbenzo[h]quinazolin-4(3H)-one    (Example 4);-   rac-3-[trans-2-hydroxycyclohexyl]-6-{[6-(1-methyl-1H-pyrazol-4-yl)pyridine-3-yl]methyl}benzo[h]quinazolin-4(3H)-one    (Example 5);-   rac-3-[trans-2-hydroxycyclohexyl]-6-{[6-(1H-pyrazol-1-yl)pyridine-3-yl]methyl}benzo[h]quinazolin-4(3H)-one    (Example 6);-   rac-5-({3-[trans-2-hydroxycyclohexyl]-4-oxo-3,4-dihydrobenzo[h]quinazolin-6-yl}methyl)pyridine-2-carbonitrile    (Example 7);-   rac-3-[trans-2-hydroxycyclohexyl]-6-{[6-methylfulfonyl)pyridine-3-yl]methyl}benzo[h]quinazolin-4(3H)-one    (Example 8);-   rac-3-[trans-2-hydroxycyclohexyl]-6-[6-methoxypyridine-3-yl)methyl]benzo[h]quinazolin-4(3H)-one    (Example 9);-   6-[(6-chloropyridin-3-yl)methyl]-3-(2-oxycyclohexy)benzo[h]quinazolin-4(3H)-one    (Example 10);-   trans-2-[6-[(6-chloropyridin-3-yl)methyl]-4-oxobenzo[h]quinazolin-3(4H)-yl]cyclohexyl    rac-acetate (Example 11);-   N-{1S,2S)-2-[6-[(6-chloropyridin-3-yl)methyl]-4-oxobenzo[h]quinazolin-3(4H)-yl]cyclohexyl}acetamide    (Example 12);-   3-[(1S,2S)-2-hydroxycyclohexyl]-6-[(6-isopropylpyridin-3-yl)methylbenzo[h]quinazolin-4(3H)-one    (Example 13);-   3-[(1S,2S)-2-hydroxycyclohexyl]-6-{[(6-(1-hydroxy-1-methylethyl)pyridin-3-yl]methyl}benzo[h]quinazolin-4(3H)-    (Example 14);-   rac-3-[trans-2-hydroxycyclohexyl]-6-{[(6-hydroxymethyl)pyridin-3-yl]methyl}benzo[h]quinazolin-4(3H)-one    (Example 15);-   rac-3-[trans-2-hydroxycyclohexyl]-6-[(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]benzo[h]quinazolin-4(3H)-one    (Example 16);-   3-[(1S,2S)-2-hydroxycyclohexyl]-6-[(6-methyl-1-oxidopyridin-3-yl)methyl]benzo[h]quinazolin-4(3H)-one    (Example 17);-   3-[(1S,2S)-2-hydroxycyclohexyl]-6-(pyridin-2-ylmethyl)benzo[h]quinazolin-4(3H)-one    (Example 18);-   6-[(6-chloropyridin-3-yl)methyl]-3-[(1S,2S)-2-hydroxycyclohexyl]-2-methylbenzo[h]quinazolin-4(3H)-one    (Example 19);-   and pharmaceutically acceptable salts thereof. Suitable    pharmaceutically acceptable salts include ammonium, sodium,    potassium, hydrochloride, hydrobromide and fumarate.

The invention is also directed to methods of treating a patient(preferably a human) for diseases or disorders in which the M1 receptoris involved, such as Alzheimer's Disease, cognitive impairment,schizophrenia, pain disorders and sleep disorders, by administering tothe patient a therapeutically effective amount of a compound of formulae(II), (III), (IV) and (IVA), or a pharmaceutically acceptable saltthereof.

The invention is also directed to the use of a compound of formulae(II), (III), (IV) and (IVA), for treating a disease or disorder in whichthe M1 receptor is involved, such as Alzheimer's Disease, cognitiveimpairment, schizophrenia, pain disorders and sleep disorders, byadministering to the patient a compound of formulae (II), (III), (IV)and (IVA), or a pharmaceutically acceptable salt thereof.

The invention is also directed to medicaments or pharmaceuticalcompositions for the treatment of diseases or disorders in a patient(preferably a human) in which the M1 receptor is involved, such asAlzheimer's Disease, cognitive impairment, schizophrenia, paindisorders, and sleep disorders, which comprise a compound of formulae(II). (Ill), (IV) and (IVA), or a pharmaceutically acceptable saltthereof, and a pharmaceutically acceptable carrier.

The invention is also directed to a method for the manufacture of amedicament or a pharmaceutical composition for treating diseases inwhich M1 receptor is involved, such as Alzheimer's Disease, cognitiveimpairment, schizophrenia, pain disorders, and sleep disorders,comprising combining a compound of formulae (II), (III), (IV) and (IVA),or a pharmaceutically acceptable salt thereof, with a pharmaceuticallyacceptable carrier.

Where a variable occurs more than once in any of formulae (II), (III),(IV) and (IVA) or in a substituent thereof, the individual occurrencesof that variable are independent of each other, unless otherwisespecified.

As used herein, the term “alkyl,” by itself or as part of anothersubstituent, means a saturated straight or branched chain hydrocarbonradical having the number of carbon atoms designated (e.g., C₁₋₁₀ alkylmeans an alkyl group having from one to ten carbon atoms). Preferredalkyl groups for use in the invention are C₁₋₆ alkyl groups, having fromone to six atoms. Exemplary alkyl groups include methyl, ethyl,n-propyl, isopropyl, n-bulyl, isobutyl, tert-butyl, pentyl, hexyl, andthe like. C₀ alkyl means a bond.

As used herein, the term “cycloalkyl,” by itself or as part of anothersubstituent, means a saturated cyclic hydrocarbon radical having thenumber of carbon atoms designated (e.g., C₃₋₁₂ cycloalkyl means acycloalkyl group having from three to twelve carbon atoms). The termcyctoalkyl as used herein includes mono-, bi- and tricyclic saturatedcarbocycles, spirocyles, and bridged and fused ring carbocycles.

Preferred cycloalkyl groups for use in the invention are monocyclic C₃₋₈cycloalkyl groups, having from three to eight carbon atoms. Exemplarymonocyclic cycloalkyl groups include cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl and the like. Exemplary bridged cycloalkylgroups include adamantyl and norbornyl. Exemplary fused cycloalkylgroups include decahydronaphthalene.

As used herein, the term “alkenyl” by itself or as part of anothersubstituent, means a straight or branched chain hydrocarbon radicalhaving a single carbon-carbon double bond and the number of carbon atomsdesignated (e.g., C₂₋₁₀ alkenyl means an alkenyl group having from twoto ten carbon atoms). Preferred alkenyl groups tor use in the inventionare C₂₋₆ alkenyl groups, having from two to six carbon atoms. Exemplaryalkenyl groups include ethenyl and propenyl.

As used herein, the term “cycloalkyl,” by itself or as part of anothersubstituent, means a saturated cyclic hydrocarbon radical having thenumber of carbon atoms designated (e.g., C₃₋₁₂ cycloalkyl means acycloalkyl group having from three to twelve carbon atoms). The termcycloalkyl as used herein includes mono-, bi- and tricyclic saturatedcarbocycles, spirocycles, and bridged and fused ring carbocycles.

Preferred cycloalkyl groups for use in the invention are monocyclic C₃₋₈cycloalkyl groups, having from three to eight carbon atoms. Exemplarymonocyclic cycloalkyl groups include cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl and the like. Exemplary bridged cycloalkylgroups include adamantyl and norbornyl. Exemplary fused cycloalkylgroups include decahydronaphthalene.

As used herein, the term “aryl,” by itself or as part of anothersubstituent, means an aromatic cyclic hydrocarbon radical. Preferredaryl groups have from six to ten carbons atoms. The term “aryl” includesmultiple ring systems as well as single ring systems. Preferred arylgroups for use in the invention include phenyl and naphthyl.

The term “aryl” also includes fused cyclic hydrocarbon rings which arepartially aromatic (i.e., one of the fused rings is aromatic and theother is non-aromatic). An exemplary aryl group which is partiallyaromatic is indanyl.

As used herein, the term “heteroaryl,” by itself or as part of anothersubstituent, means a cyclic or polycyclic group having from five totwelve ring atoms selected from C, N, O and S, wherein at least one ringheteroatom is O, N or S, and wherein at least one of the constituentrings is aromatic. Exemplary heteroaryl groups for use in the inventioninclude carbazolyl, carbolinlyl, chromenyl, cinnolinyl, furanyl,benzofuranyl, benzofurazanyl, isobenzofuranyl, imidazolyl,benzimidszolyl, benzimidazolonyl, indazolyl, indolyl, isoindolyl,indolinyl, indolazinyl, indynyl, oxadiazolyl, oxazolyl, benzoxazolyl,isoxazolyl, pyranyl, pyrazinyl, pyrazolyl, benzopyrazolyl, pyridazinyl,pyridyl, pyrimidinyl, pyrrolyl, quinolyl, isoquinolyl, tetrazolyl,thiazolyl, isothiazolyl, thiadiazolyl, thienyl, benzothioenyl,benzothiazolyl, quinoxalinyl, triazinyl and triazolyl, and N-oxidesthereof.

In one such embodiment, the heteroaryl groups have 5 or 6 ring atoms.

For example, one subgroup of heteroaryl groups have 5 or 6 ring atomsand a single heteroatom, which is nitrogen. Exemplary heteroaryl groupsin this embodiment are pyridyl and pyrrolyl.

Another subgroup of heteroaryl groups have 5 or 6 ring atoms and twoheteroatoms, which are selected from sulfur and nitrogen. Exemplaryheteroaryl groups in this embodiment are pyrazolyl, imidazolyl andthienyl.

Another subgroup of heteroaryl groups have 5 or 6 ring atoms and threeheteroatoms, which are selected from sulfur and nitrogen. An exemplaryheteroaryl group in this embodiment includes triazolyl.

Another subgroup of heteroaryl groups have 7, 8 or 9 ring atoms and twoheteroatoms, which are selected from oxygen, sulfur and nitrogen.Exemplary heteroaryl groups in this embodiment are indazole andazaindolizine.

The term “heteroaryl” also includes fused cyclic heterocyclic ringswhich are partially aromatic (i.e., one of the fused rings is aromaticand the other is non-aromatic). An exemplary heteroaryl group which ispartially aromatic is benzodioxol.

When a heteroaryl group as defined herein is substituted, thesubstituent may be bonded to a ring carbon atom of the heteroaryl group,or on a ring heteroatom (i.e., a nitrogen, oxygen or sulfur), which hasa valence which permits substitution. Preferably, the substituent isbonded to a ring carbon atom. Similarly, when a heteroaryl group isdefined as a substituent herein, the point of attachment may be at aring carbon atom of the heteroaryl group, or on a ring heteroatom (i.e.,a nitrogen, oxygen or sulfur), which has a valence which permitsattachment. Preferably, the attachment is at a ring carbon atom.

As used herein, the term “heterocyclic,” by itself or as part of anothersubstituent, means a cycloalkyl group as defined above, in which one ormore of the ring carbon atoms is replaced with a heteroatom (such as N,S or O). Suitable non-aromatic heterocyclic groups for use in theinvention include piperidinyl piperazinyl, morpholinyl, thiomorpholinyl,tetrahydropyranyl tetrahydrofuranyl and tetrahyropyrazopyrimidine.Preferred heterocyclic groups for use in the invention have four toeight ring atoms and a single nitrogen or oxygen heteroatom.

When a heterocyclic group as defined herein is substituted, thesubstituent may be bonded to a ring carbon atom of the heterocyclicgroup, or to a ring heteroatom (i.e., a nitrogen, oxygen or sulfur),which has a valence which permits substitution. Preferably, thesubstituent is bonded to a ring carbon atom. Similarly, when aheterocyclic group is defined as a substituent herein, the point ofattachment may be at a ring carbon atom of the heterocyclic group, or ona ring heteroatom (i.e., a nitrogen, oxygen or sulfur), which has avalence which permits attachment. Preferably, the attachment is at aring carbon atom.

As used herein, the term “halo” or “halogen” includes fluoro, chloro,bromo and iodo.

The compounds of the invention may have one or more asymmetric centers.Compounds with asymmetric centers give rise to enantiomers (opticalisomers), diastereomers (configurational isomers) or both, and it isintended that all of the possible enantiomers and diastereomers inmixtures and as pure or partially purified compounds are included withinthe scope of this invention. The present invention is meant to encompassall such isomeric forms of the compounds of formulae (I), (II), (III),(IV) and (IVA).

Formulae (I), (II), (III), (IV) and (IVA) are shown above without adefinite stereochemistry. The present invention includes allstereoisomers of formulae (I), (II), (III), (IV) and (IVA) andpharmaceutically acceptable salts thereof.

The independent syntheses of the enantiomerically or diastercomericallyenriched compounds, or their chromatographic separations, may beachieved as known in the art by appropriate modification of themethodology disclosed herein. Their absolute stereochemistry may bedetermined by the x-ray crystallography of crystalline products orcrystalline intermediates that are derivatized, if necessary, with areagent containing an asymmetric center of known absolute configuration.

If desired, racemic mixtures of the compounds may be separated so thatthe individual enantiomers or diastercomers are isolated. The separationcan be carried out by methods well known in the art, such as thecoupling of a racemic mixture of compounds to an enantiomerically purecompound to form a diastereomeric mixture, followed by separation of theindividual diastercomers by standard methods, such as fractionalcrystallization or chromatography. The coupling reaction is often theformation of salts using an enantiomerically pure acid or base. Thediastercomeric derivatives may then be converted to the pure enantiomersby cleavage of the added chiral residue. The racemic mixture of thecompounds can also be separated directly by chromatographic methodsusing chiral stationary phases, which methods are well known in the art.

Alternatively, any enantiomer or diastercomer of a compound may beobtained by stereoselective synthesis using optically pure startingmaterials or reagents of known configuration by methods well known inthe art.

The compounds of the invention may be prepared according to thefollowing reaction Schemes, in which variables are as defined before orare derived, using readily available starting materials, from reagentsand conventional synthetic procedures. It is also possible to usevariants which are themselves known to those of ordinary skill inorganic synthesis art, but are not mentioned in greater detail.

The present invention also provides a method for the synthesis ofcompounds useful as intermediates in the preparation of compounds of theinvention.

During any of the above synthetic sequences it may be necessary ordesirable to protect sensitive or reactive groups on any of themolecules concerned. This may be achieved by means of conventionalprotecting groups, such as those described in Protective Groups inOrganic Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973, and T. W.Greene & P/G. M. Wuts. Protective Groups in Organic Synthesis, JohnWiley & Sons, 1999. The protecting groups may be removed at a convenientsequent stage using methods known from the art.

Specific embodiments of the compounds of the invention, and methods ofmaking them, are described in the Examples herein.

The term “substantially pure” means that the isolated material is atleast 90% pure, and preferably 95% pure, and even more preferably 99%pure as assayed by analytical techniques known in the art.

As used herein, the term “muscarinic M1 receptor” refers to one of thefive subtypes of the muscarinic acetylcholine receptor, which is fromthe superfamily of G-protein coupled receptors. The family of muscarinicreceptors is described, for example, in Pharmacol Ther, 1993,58:319-379; Eur J Pharmacol, 1906,295:93-102, and Mol Pharmacol, 2002,61:1297-1302. The muscarinic receptors are known to contain one or moreallosteric sites, which may alter the affinity with which muscarinicligands bind to the primary binding or orthosteric sites. See, e.g., S.Lazareno et al. Mol Pharmacol, 2002, 62:6, 1491-1505.

As used herein, the terms “positive allosteric modulator” and“allosteric potentiator” are used interchangeably, and refer to a ligandwhich interacts with an allosteric site of a receptor to activate theprimary binding site. The compounds of the invention are positiveallosteric modulators of the muscarinic M1 receptor. For example, amodulator or potentiator may directly or indirectly augment the responseproduced by the endogenous ligand (such as acetylcholine or xanomeline)at the orthosteric site of the muscarinic M1 receptor in an animal, inparticular, a human.

The actions of ligands at allosteric receptor sites may also beunderstood according to the “allosteric ternary complex model,” as knownby those skilled in the art. The allosteric ternary complex model isdescribed with respect to the family of muscarinic receptors in Birdsallet al, Life Sciences, 2001, 68:2517-2524. For a general description ofthe role of allosteric binding sites, see Christopoulos, Nature Reviews:Drug Discovery, 2002, 1:198-210.

It is believed that the compounds of the invention bind to an allostericbinding site that is distinct from the orthosteric acetylcholine site ofthe muscarinic M1 receptor, thereby augmenting the response produced bythe endogenous ligand acetylcholine at the orthosteric site of the M1receptor. It is also believed that the compounds of the invention bindto an allosteric site which is distinct from the xanomeline site of themuscarinic M1 receptor, thereby augmenting the response produced by theendogenous ligand xanomeline at the orthosteric site of the M1 receptor.

The term “pharmaceutically acceptable salts” refers to salts preparedfrom pharmaceutically acceptable non-toxic bases or acids includinginorganic or organic bases and inorganic or organic acids. The compoundsof the invention may be mono, di or tris salts, depending on the numberof acid functionalities present in the free base form of the compound.Free bases and salts derived from inorganic bases include aluminum,ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganicsalts, manganous, potassium, sodium, zinc, and the like.

Salts in the solid form may exist in more than one crystal structure,and may also be in the form of hydrates. Salts derived frompharmaceutically acceptable organic non-toxic bases include salts ofprimary, secondary, and tertiary amines, substituted amines includingnaturally occurring substituted amines, cyclic amines, and basic ionexchange resins, such as arginine, betaine, caffeine, choline,N,N′-dibenzylethylene-diamine, diethylamine, 2-diethylaminoethanol,2-dimethylaminoethanol, ethanolamine, ethylenediamine,N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine,hydrabamine, isoropylamine, lysine, methylglucamine, morpholine,piperazine, piperidine, polyamine resins, procaine, purines,theobromine, triethylamine, trimethylamine, tripropylamine,tromethamine, and the like.

When the compound of the present invention is basic, salts may beprepared from pharmaceutically acceptable non-toxic acids, includinginorganic and organic acids. Such acids include acetic, trifluoroacetic,benenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic,fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic,lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic,pantothenic, phosphoric, succinic, sulfuric, tartaric,para-toluenesulfonic acid, and the like.

The present invention is directed to the use of the compounds offormulae (I), (II), (III), (IV) and (IVA) disclosed herein as M1allosteric modulators in a patient or subject such as a mammal in needof such activity, comprising the administration of an effective amountof the compound. In addition to humans, a variety of other mammals canbe treated according to the method of the present invention.

The compounds of the present invention have utility in treating orameliorating Alzheimer's disease. The compounds may also be useful intreating or ameliorating other diseases mediated by the muscarinic M1receptor, such as schizophrenia, sleep disorder, pain disorders(including acute pain, inflammatory pain and neuropathic pain) andcognitive disorders (including mild cognitive impairment). Otherconditions that may be treated by the compounds of the invention includeParkinson's Disease, pulmonary hypertension, chronic obstructivepulmonary disease (COPD), asthma, urinary incontinence, glaucoma,schizophrenia, Trisomy 21 (Down Syndrome), cerebral amyloid angiopathy,degenerative dementia. Hereditary Cerebral Hemorrhage with Amyloidosisof the Dutch-Type (HCHWA-D), Creutzfeld-Jakob disease, prion disorders,amyotrophic lateral sclerosis, progressive supranuclear palsy, headtrauma, stroke, pancreatitis, inclusion body myositis, other peripheralamytoidoses, diabetes, autism and atherosclerosis.

In preferred embodiments, the compounds of the invention are useful intreating Alzheimer's Disease, cognitive disorders, schizophrenia, paindisorders and sleep disorders. For example, the compounds may be usefulfor the prevention of dementia of the Alzheimer's type, as well as forthe treatment of early stage, intermediate stage or late stage dementiaof the Alzheimer's type.

Potential schizophrenia conditions or disorders for which the compoundsof the invention may be useful include one or more of the followingconditions or diseases: schizophrenia or psychosis includingschizophrenia (paranoid, disorganized, catatonic or undifferentiated),schizophreniform disorder, schizoaffective disorder, delusionaldisorder, brief psychotic disorder, shared psychotic disorder, psychoticdisorder due to a general medical condition and substance-induced ordrug-induced (phencyclidine, ketanine and other dissociativeanaesthetics, amphetamine and other psychostimulants and cocaine)psychosispsychotic disorder, psychosis associated with affectivedisorders, brief reactive psychosis, schizoaffective psychosis,“schizophrenia-spectrum” disorders such as schizoid or schizotypalpersonality disorders, or illness associated with psychosis (such asmajor depression, manic depressive (bipolar) disorder, Alzheimer'sdisease and post-traumatic stress syndrome), including both the positiveand the negative symptoms of schizophrenia and other psychoses;cognitive disorders including dementia (associated with Alzheimer'sdisease, ischemia, multi-infarct dementia, trauma, vascular problems orstroke, HIV disease, Parkinson's disease. Huntington's disease, Pick'sdisease, Creutzfeldt-Jacob disease, perinatal hypoxia, other generalmedical conditions or substance abuse); delirium, amnestic disorders orage related cognitive decline.

In another specific embodiment, the present invention provides a methodfor treating schizophrenia or psychosis comprising administering to apatient in need thereof an effective amount of a compound of the presentinvention. Particular schizophrenia or psychosis pathologies areparanoid, disorganized, catatonic or undifferentiated schizophrenia andsubstance-induced psychotic disorder. At present, the text revision ofthe fourth edition of the Diagnostic and Statistical Manual of MentalDisorders (DSM-IV-TR) (2000, American Psychiatric Association,Washington DC) provides a diagnostic tool that includes paranoid,disorganized, catatonic or undifferentiated schizophrenia andsubstance-induced psychotic disorder. As used herein, the term“schizophrenia or psychosis” includes treatment of those mentaldisorders as described in DSM-IV-TR. The skilled artisan will recognizethat there are alternative nomenclatures, nosologies and classificationsystems for mental disorders, and that these systems evolve with medicaland scientific progress. Thus the term “schizophrenia or psychosis” isintended to include like disorders that are described in otherdiagnostic sources.

Examples of combinations of the compounds include combinations withagents for the treatment of schizophrenia, for example in combinationwith sedatives, hypnotics, anxiolytics, antipsychotics, antianxietyagents, cyclopyrrolones, imidazopyridines, pyrazolopyrimidines. minortranquilizers, melatonin agonist and antagonist, melatonergic agents,benzodiazepines, barbiturates. 5HT-2 antagonists, and the like, such as:adinazolam, allobarbital, alonimid, aiprazolam, amisulpride,amitriptyline, amobarbital, amoxapine, aripiprazole, bentazepam,benzoctamine, brotizolam, bupropion, busprione, butabarbital,butalbital, capuride, carbocloral, chloral betaine, chloral hydrate,clomipramine, clonazepam, cloperidone, clorazepate, chlordiazepoxide,clorethate, chlorpromazine, clozapine, cyprazepam, desipramine,dexclamol, diazepam, dichloralphenazone, divalproex, diphenhydramine,doxepin, estazolam, ethchlorvynol, etomidate, fenobam, flunitrazepam,flupentixol, fluphenazine, flurazepam, fluvoxamine, fluoxetine,fosazepam, glutethimide, halazepam, haloperidol, hydroxyzine,imipramine, lithium, lorazepam, lormetazepam, maprotiline, mecloqualone,melatonin, mephobarbital, meprobamate, methaqualone, midaflur,midazolam, nefazodone, nisobamate, nitrazepam, nortriptyline,olanzapine, oxazepam, paraldehyde, paroxetine, pentobarbital, perlapine,perphenazine, phenelzine, phenobarbital, prazepam, promethazine,propofol, protripyline, quazepam, quetiapine, reclazepam, risperidone,roletamide, secobarbital, sertraline, suproelone, temazepam,thioridazine, thiothixene, tracazolate, tranylcypromaine, trazodone,triazolam, trepipam, tricetamide, triclofos, trifluoperazine,trimetozine, trimipramine, uldazepam, venlafaxine, zaleplon,ziprasidone, zolazepam, zolpidem, and salts thereof, and combinationsthereof, and the like, or the subject compound may be administered inconjunction with the use of physical methods such as with light therapyor electrical stimulation.

In another embodiment, the subject compound may be employed incombination with levodopa (with or without a selective extracerebraldecarboxylase inhibitor such as carbidopa or benserazide),anticholinergics such as biperiden (optionally as its hydrochloride orlactate salt) and trihexyphenidyl (benzhexol) hydrochloride, COMTinhibitors such as entacapone, MOA-B inhibitors, antioxidants, A2aadenosine receptor antagonists, cholinergic agonists, NMDA receptorantagonists, serotonin receptor antagonists and dopamine receptoragonists such as alenlemol, bromocriptine, fenoldopam, lisuride,naxagolide, pergolide and pramipexole. It will be appreciated that thedopamine agonist may be in the form of a pharmaceutically acceptablesalt, for example, alentemol hydrobromide, bromocriptine mesylate,fenoldopam mesylate, naxagolide hydrochloride and pergolide mesylate.

In another embodiment, the subject compound may be employed incombination with a compound from the phenothiazine, thioxanthene,heterocyclic dibenzazepine, butyrophenone, diphenylbutylpiperidine andindolone classes of neuroleptic agent. Suitable examples ofphenothiazines include chlorpromazine, mesoridazine, thioridazine,acetophenazine, fluphenazine, perphenazine and trifluoperazine. Suitableexamples of thioxanthenes include chlorprothixene and thiothixene. Anexample of a dibenzazepine is clozapine. An example of a butyrophenoneis haloperidol. An example of a diphenylbutylpiperidine is pimozide. Anexample of an indolone is molindolone. Other neuroleptic agents includeloxapine, sulpiride and risperidone. It will be appreciated that theneuroleptic agents when used in combination with the subject compoundmay be in the form of a pharmaceutically acceptable salt, for example,chlorpromazine hydrochloride, mesoridazine besylafe, thioridazinehydrochloride, acetophenazine maleate, fluphenazine hydrochloride,flurphenazine enathate, fluphenazine decanoate, trifluoperazinehydrochloride, thiothixene hydrochloride, haloperidol decanoate,loxapine succinate and molindone hydrochloride. Perphenazine,chlorprothixene, clozapine, haloperidol, pimozide and risperidone arecommonly used in a non-salt form. Thus, the subject compound may beemployed in combination with acetophenazine, alentemol, aripiprazole,amisuipride, benzhexol, bromocriptine, biperiden, chlorpromazine,chlorprothixene, clozapine, diazepam, fenoldopam, fluphenazine,haloperidol, levodopa, levodopa with benserazide, levodopa withcarbidopa, lisuride, loxapine, mesoridazine, molindolone, naxagolide,olanzapine, pergolide, perphenazine, pimozide, pramipexole, quetiapine,risperidone, sulpiride, tetrabenazine, frihexyphenidyl, thioridazine,thiothixene, trifluoperazine or ziprasidone.

Potential sleep conditions or disorders for which the compounds of theinvention may be useful include enhancing sleep quality; improving sleepquality; augmenting sleep maintenance; increasing the value which iscalculated from the time that a subject sleeps divided by the time thata subject is attempting to sleep; decreasing sleep latency or onset (thetime it takes to fall asleep); decreasing difficulties in fallingasleep; increasing sleep continuity; decreasing the number of awakeningsduring sleep; decreasing nocturnal arousals: decreasing the time spentawake following the initial onset of sleep; increasing the total amountof sleep; reducing the fragmentation of sleep; altering the timing,frequency or duration of REM sleep bouts; altering the timing, frequencyor duration of slow wave (i.e. stages 3 or 4) sleep bouts; increasingthe amount and percentage of stage 2 sleep; promoting slow wave sleep;enhancing EEG-delta activity during sleep; increasing daytime alertness;reducing daytime drowsiness; treating or reducing excessive daytimesleepiness; insomnia; hypersomnia; narcolepsy; interrupted sleep; sleepapnea; wakefulness; nocturnal myoclonus; REM sleep interruptions;jet-lag; shift workers' sleep disturbances; dyssomnias; night terror;insomnias associated with depression, emotional/mood disorders, as wellas sleep walking and enuresis, and sleep disorders which accompanyaging; Alzheimer's sundowning; conditions associated with circadianrhythmicity as well as mental and physical disorders associated withtravel across time zones and with rotating shift-work schedules;conditions due to drugs which cause reductions in REM sleep as a sideeffect; syndromes which are manifested by non-restorative sleep andmuscle pain or sleep apnea which is associated with respiratorydisturbances during sleep: and conditions which result from a diminishedquality of sleep.

Pain disorders for which the compounds of the invention may be usefulinclude neuropathic pain (such as postherpetic neuralgia, nerve injury,the “dynias”, e.g., vulvodynia, phantom limb pain, root avulsions,painful diabetic neuropathy, painful traumatic mononeuropathy, painfulpolyneuropathy); central pain syndromes (potentially caused by virtuallyany lesion at any level of the nervous system); postsurgical painsyndromes (eg, postmastectomy syndrome, postthoracotomy syndrome, stumppain); bone and joint pain (osteoarthritis), repetitive motion pain,dental pain, cancer pain, myofascial pain (muscular injury,fibromyalgia); perioperative pain (general surgery, gynecological),chronic pain, dysmennorhea, as well as pain associated with angina, andinflammatory pain of varied origins (e.g. osteoarthritis, rheumatoidarthritis, rheumatic disease, teno-synovitis and gout), headache,migraine and cluster headache, headache, primary hyperalgesia, secondaryhyperalgesia, primary allodynia, secondary allodynia, or other paincaused by central sensitization.

Compounds of the invention may also be used to treat or preventdyskinesias. Furthermore, compounds of the invention may be used todecrease tolerance and/or dependence to opioid treatment of pain, andfor treatment of withdrawal syndrome of e.g., alcohol, opioids, andcocaine.

The subject or patient to whom the compounds of the present invention isadministered is generally a human being, male or female, in whom M1allosteric modulation is desired, but may also encompass other mammals,such as dogs, cats, mice, rats, cattle, horses, sheep, rabbits, monkeys,chimpanzees or other apes or primates, for which treatment of the abovenoted disorders is desired.

The compounds of the present invention may be used in combination withone or more other drugs in the treatment of diseases or conditions forwhich the compounds of the present invention have utility, where thecombination of the drugs together are safer or more effective thaneither drug alone. Additionally, the compounds of the present inventionmay be used in combination with one or more other drugs that treat,prevent, control, ameliorate, or reduce the risk of side effects ortoxicity of the compounds of the present invention. Such other drugs maybe administered, by a route and in an amount commonly used therefor,contemporaneously or sequentially with the compounds of the presentinvention. Accordingly, the pharmaceutical compositions of the presentinvention include those that contain one or more other activeingredients, in addition to the compounds of the present invention. Thecombinations may be administered as part of a unit dosage formcombination product, or as a kit or treatment protocol wherein one ormore additional drugs are administered in separate dosage forms as partof a treatment regimen.

Examples of combinations of the compounds of the present inventioninclude combinations with anti-Alzheimer's Disease agents, for examplebeta secretase inhibitors; alpha 7 nicotinic agonists, such as ABT089,SSR180711 and MEM63908; ADAM 10 ligands or activators; gamma-secretaseinhibitors, such as LY450139 and TAK 070; gamma secretase modulators;tau phosphorylation inhibitors; glycine transport inhibitors; LXR βagonists; ApoE4 conformational modulators; NR2B antagonists; androgenreceptor modulators: blockers of Aβ oligomer formation; 5-HT4 agonists,such as PRX-03140; 5-HT6 antagonists, such as GSK 742467, SGS-518,FK-962, SL-65.0155, SRA-333 and xaliproden; 5-HT1a antagonists, such aslecozotan; p25/CDK5 inhibitors; NK1/NK3 receptor antagonists: COX-2inhibitors; HMG-CoA reductase inhibitors; NSAIDs including ibuprofen;vitamin E; anti-amyloid antibodies (including anti-amyloid humanizedmonoclonal antibodies), such as bapineuzumab, ACC001, CAD106, AZD3102,H12A11V1; anti-inflammatory compounds such as (R)-flurbiprofen,nitroflurbiprofen, ND-1251, VP-025, HT-0712 and EHT-202; PPAR gammaagonists, such as pioglitazone and rosiglitazone; CB-1 receptorantagonists or CB-1 receptor inverse agonists, such as AVE1625;antibiotics such as doxycycline and rifampin; N-methyl-D-aspartate(NMDA) receptor antagonists, such as memantine, neramexane and EVT101;cholinesterase inhibitors such as galantamine, rivastigmine, donepezil,tacrine, phenserine, ladostigil and ABT-089; growth hormonesecretagogues such as ibutamoren, ibutamoren mesylate, and capromorelin;histamine H₃ receptor antagonists such as ABT-834, ABT 829, GSK 189254and CEP16795; AMPA agonists or AMPA modulators, such as CX-717, LY451395, LY404187 and S-18986; PDE IV inhibitors, including MEM1414,HT0712 and AVE8112; GABA_(A) inverse agonists; GSK3β inhibitors,including AZD1080, SAR502250 and CEP16805; neuronal nicotinic agonists;selective M1 agonists; HDAC inhibitors; and microtubule affinityregulating kinase (MARK) ligands; or other drugs that affect receptorsor enzymes that either increase the efficacy, safety, convenience, orreduce unwanted side effects or toxicity of the compounds of the presentinvention.

Examples of combinations of the compounds include combinations withagents for the treatment of pain, for example non-steroidalanti-inflammatory agents, such as aspirin, diclofenac, duflunisal,fenoprofen, flurbiprofen, ibuprofen, indomethacin, ketoprofen,ketorolac, naproxen, oxaprozin, piroxicam, sulindac and tolmetin; COX-2inhibitors, such as celecoxib, rofecoxib, valdecoxib, 406381 and 644784;CB-2 agonists, such as 842166 and SAB378; VR-1 antagonists, such asAMG517, 705498, 782443, PAC20030, V114380 and A425619; bradykinin B1receptor antagonists, such as SSR240612 and NVPSAA164; sodium channelblockers and antagonists, such as VX409 and SP1860; nitric oxidesynthase (NOS) inhibitors (including iNOS and nNOS inhibitors), such asSD6010 and 274150; glycine site antagonists, including lacosamide;neuronal nicotinic agonists, such as ABT 894; NMDA antagonists, such asAZD4282; potassium channel openers; AMPA/kainate receptor antagonists;calcium channel blockers, such as ziconotide and NMED160; GABA-Areceptor IO modulators (e.g., a GABA-A receptor agonist); matrixmetalloprotease (MMP) inhibitors; thrombolytic agents; opioid analgesicssuch as codeine, fentanyl, hydromorphone, levorphanol, meperidine,methadone, morphine, oxycodone, oxymorphone, pentazocine, propoxyphene;neutrophil inhibitory factor (NIF); pramipexole, ropinirole;anticholinergics; amantadine; monoamine oxidase B15 (“MAO-B”)inhibitors; 5HT receptor agonists or antagonists; mGlu5 antagonists,such as AZD9272; alpha agonists, such as AGNXX/YY; neuronal nicotinicagonists, such as ABT894; NMDA receptor agonists or antagonists, such asAZD4282; NKI antagonists; selective serotonin reuptake inhibitors(“SSRI”) and/or selective serotonin and norepinephrine reuptakeinhibitors (“SSNRI”), such as duloxetine; tricyclic antidepressantdrugs, norepinephrine modulators; lithium; valproate: gabapentin;pregabalin; rizatriptan; zolmitriptan; naratriptan and sumatriptan.

The compounds of the present invention may be administered incombination with compounds useful for enhancing sleep quality andpreventing and treating sleep disorders and sleep disturbances,including e.g., sedatives, hypnotics, anxiolytics, antipsychotics,antianxiety agents, antihistamines, benzodiazepines, barbiturates,cyclopyrrolones, orexin antagonists, alpha-1 antagonists, GABA agonists,5HT-2 antagonists including 5HT-2A antagonists and 5HT-2A/2C antagonist,histamine antagonists including histamine H3 antagonists, histamine H3inverse agonists, imidazopyridines, minor tranquilizers, melatoninagonists and antagonists, melatonergic agents, other orexin antagonists,orexin agonist, prokineticin agonists and antagonists,pyrazolopyrimidines, T-type calcium channel antagonise,triazolopyridines, and the like, such as: adinazolam, allobarbital,alonimid, alprazolam, amitriptyline, amobarbital, amoxapine,armodafinil, APD-125, bentazepam, benzoctamine, brotizolam, bupropion,busprione, butabarbital, butalbital, capromorelin, capuride,carbocloral, chloral betaine, chloral hydrate, chlordiazepoxide,clomipramine, clonazepam, cloperidone, clorazepate, clorethate,clozapine, conazepam, cyprazepam, desipramine, dexclamol, diazepam,dichloralphenazone, divalproex, diphenhydramine, doxepin, EMD-281014,eplivanserin, estazolam, eszopiclone, ethchlorynol, etomidate, fenobam,flunitrazepam, flurazepam, fluvoxamine, fluoxetine, fosazepam,gaboxadol, glutethimide, halazepam, hydroxyzine, ibutamoren, imipramine,indiplon, lithium, lorazepam, lormetazepam, LY-156735, maprotiline,MDL-100907, mecloqualone, melatonin, mephobarbital, meprobamate,methaqualone, methyprylon, midaflur, midazolam, modafinil, nefazodone,NGD-2-73, nisobamate, nitrazepam, nortriptyline, oxazepam, paraldehyde,paroxetine, pentobarbital, perlapine, perphenazine, phenelzine,phenobarbital, prazepam, promethazine, propofol, protriptyline,quazepam, ramelteon, reclazepam, roletamide, secobarbital, sertraline,suproclone, TAK-375, ternazepam, thioridazine, tiagabine, tracazolate,tranylcypromaine, trazodone, triazolam, trepipam, tricetamide,triclofos, trifluoperazine, trimetozine, trimipramine, uldazepam,venlafaxine, zaleplon, zolazepam, zopiclone, zolpidem, and saltsthereof, and combinations thereof, and the like, or the compound of thepresent invention may be administered in conjunction with the use ofphysical methods such as with light therapy or electrical stimulation.

In another embodiment, the subject compound may be employed incombination with levodopa (with or without a selective extracerebraldecarboxylase inhibitor such as carbidopa or benserazide),anticholinergics such as biperiden (optionally as its hydrochloride orlactate salt) and trihexyphenidyl (benzhexol) hydrochloride, COMTinhibitors such as entacapone, MOA-B inhibitors, antioxidants, A2aadenosine receptor antagonists, cholinergic agonists and dopaminereceptor agonists such as alentemol, bromocriptine, fenoldopam,lisuride, naxagolide, pergolide and pramipexole.

The term “composition” as used herein is intended to encompass a productcomprising specified ingredients in predetermined amounts orproportions, as well as any product which results, directly orindirectly, from combination of the specified ingredients in thespecified amounts. This term in relation to pharmaceutical compositionsis intended to encompass a product comprising one or more activeingredients, and an optional carrier comprising inert ingredients, aswell as any product which results, directly or indirectly, fromcombination, complexation or aggregation of any two or more of theingredients, or from dissociation of one or more of the ingredients, orfrom other types of reactions or interactions of one or more of theingredients.

In general, pharmaceutical compositions are prepared by uniformly andintimately bringing the active ingredient into association with a liquidcarrier or a finely divided solid carrier or both, and then, ifnecessary, shaping the product into the desired formulation. In thepharmaceutical composition the active compound, which is a compound offormulae (I) to (VIII), is included in an amount sufficient to producethe desired effect upon the process or condition of diseases.Accordingly, the pharmaceutical compositions of the present inventionencompass any composition made by admixing a compound of the presentinvention and a pharmaceutically acceptable carrier.

The carrier may take a wide variety of forms depending on the form ofpreparation desired for administration, e.g., oral or parenteral(including intravenous). Thus, the pharmaceutical competitions of thepresent invention can be presented as discrete units suitable for oraladministration such as capsules, cachets or tablets each containing apredetermined amount of the active ingredient. Further, the compositionscan be presented as a powder, as granules, as a solution, as asuspension in an aqueous liquid, as a non-aqueous liquid, as anoil-in-water emulsion or as a water-in-oil liquid emulsion. In additionto the common dosage forms set out above, the compounds of theinvention, or pharmaceutically acceptable salts thereof, may also beadministered by controlled release means and/or delivery devices.

Pharmaceutical compositions intended for oral use may be preparedaccording to any method known to the art for the manufacture ofpharmaceutical compositions and such compositions may contain one ormore agents selected from the group consisting of sweetening agents,flavoring agents, coloring agents and preserving agents in order toprovide pharmaceutically elegant and palatable preparations. Tablets maycontain the active ingredient in admixture with non-toxicpharmaceutically acceptable excipients which are suitable for themanufacture of tablets. These excipients may be, for example, inertdiluents, such as calcium carbonate, sodium carbonate, lactose, calciumphosphate or sodium phosphate; granulating and disintegrating agents,for example, corn starch, or alginic acid; binding agents, for examplestarch, gelatin or acacia, and lubricating agents, for example magnesiumstearate, stearic acid or talc. The tablets may be uncoated or they maybe coated by known techniques to delay disintegration and absorption inthe gastrointestinal tract and thereby provide a sustained action over alonger period.

A tablet containing the composition of this invention may be prepared bycompression or molding, optionally with one or more accessoryingredients or adjuvants. Compressed tablets may be prepared bycompressing, in a suitable machine, the active ingredient in afree-flowing form such as powder or granules, optionally mixed with abinder, lubricant, inert diluent, surface active or dispersing agent.Molded tablets may be made by molding in a suitable machine, a mixtureof the powdered compound moistened with an inert liquid diluent. Eachtablet preferably contains from about 0.1 mg to about 500 mg of theactive ingredient and each cachet or capsule preferably containing fromabout 0.1 mg to about 500 mg of the active ingredient.

Compositions for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules wherein the active ingredient is mixed with water or anoil medium, for example peanut oil, liquid paraffin, or olive oil.

Other pharmaceutical compositions include aqueous suspensions, whichcontain the active materials in admixture with excipients suitable forthe manufacture of aqueous suspensions. In addition, oily suspensionsmay be formulated by suspending the active ingredient in a vegetableoil, for example arachis oil, olive oil, sesame oil or coconut oil, orin a mineral oil such as liquid paraffin. Oily suspensions may alsocontain various excipients. The pharmaceutical compositions of theinvention may also be in the form of oil-in-water emulsions, which mayalso contain excipients such as sweetening and flavoring agents.

The pharmaceutical compositions may be in the form of a sterileinjectable aqueous or oleaginous suspension, or in the form of sterilepowders for the extemporaneous preparation of such sterile injectablesolutions or dispersions. In all cases, the final injectable form mustbe sterile and must be effectively fluid for easy syringability. Thepharmaceutical compositions must be stable under the conditions ofmanufacture and storage; thus, preferably should be preserved againstthe contaminating action of microorganisms such as bacteria and fungi.

Pharmaceutical compositions of the present invention can be in a formsuitable for topical use such as, for example, an aerosol, cream,ointment, lotion, dusting powder, or the like. Further, the compositionscan be in a form suitable for use in transdermal devices. Theseformulations may be prepared via conventional processing methods. As anexample, a cream or ointment is prepared by mixing hydrophilic materialand water, together with about 5 wt % to about 10 wt % of the compound,to produce a cream or ointment having a desired consistency.

Pharmaceutical compositions of this invention can also be in a formsuitable for rectal administration wherein the carrier is a solid. It ispreferable that the mixture forms unit dose suppositories. Suitablecarriers include cocoa butter and other materials commonly used in theart.

By “pharmaceutically acceptable” it is meant the carrier, diluent orexcipient must be compatible with the other ingredients of theformulation and not deleterious to the recipient thereof.

The terms “administration of” or “administering a” compound should beunderstood to mean providing a compound of the invention to theindividual in need of treatment in a form that can be introduced intothat individual's body in a therapeutically useful form andtherapeutically useful amount, including, but not limited to: oraldosage forms, such as tablets, capsules, syrups, suspensions, and thelike; injectable dosage forms, such as IV, IM, or IP, and the like;transdermal dosage forms, including creams, jellies, powders, orpatches: buccal dosage forms; inhalation powders, sprays, suspensions,and the like; and rectal suppositories.

The terms “effective amount” or “therapeutically effective amount” meansthe amount of the subject compound that will elicit the biological ormedical response of a tissue, system, animal or human that is beingsought by the researcher, veterinarian, medical doctor or otherclinician.

As used herein, the term “treatment” or “treating” means anyadministration of a compound of the present invention and includes (1)inhibiting the disease in an animal that is experiencing or displayingthe pathology or symptomatology of the diseased (i.e., arresting furtherdevelopment of the pathology and/or symptomatology), or (2) amelioratingthe disease in an animal that is experiencing or displaying thepathology or symptomatology of the diseased (i.e., reversing thepathology and or symptomatology).

The compositions containing compounds of the present invention mayconveniently be presented in unit dosage form and may be prepared by anyof the methods well known in the art of pharmacy. The term “unit dosageform” is taken to mean a single dose wherein all active and inactiveingredients are combined in a suitable system, such that the patient orperson administering the drug to the patient can open a single containeror package with the entire dose contained therein, and does not have tomix any components together from two or more containers or packages.Typical examples of unit dosage forms are tablets or capsules for oraladministration, single dose vials for injection, or suppositories forrectal administration. This list of unit dosage forms is not intended tobe limiting in any way, but merely to represent typical examples of unitdosage forms.

The compositions containing compounds of the present invention mayconveniently be presented as a kit, whereby two or more components,which may be active or inactive ingredients, carriers, diluents, and thelike, are provided with instructions for preparation of the actualdosage form by the patient or person administering the drug to thepatient. Such kits may be provided with all necessary materials andingredients contained therein, or they may contain instructions forusing or making materials or components that must be obtainedindependently by the patient or person administering the drug to thepatient.

When treating or ameliorating a disorder or disease for which compoundsof the present invention are indicated, generally satisfactory resultsare obtained when the compounds of the present invention areadministered at a daily dosage of from about 0.1 mg to about 100 mg perkg of animal body weight, preferably given as a single daily dose or individed doses two to six times a day, or in sustained release form. Thetotal daily dosage is from about 1.0 mg to about 2000 mg, preferablyfrom about 0.1 mg to about 20 mg per kg of body weight. In the case of a70 kg adult human, the total daily dose will generally be from about 7mg to about 1,400 mg. This dosage regimen may be adjusted to provide theoptimal therapeutic response. The compounds may be administered on aregimen of 1 to 4 times per day, preferably Once or twice per day.

The amount of active ingredient that may be combined with the carriermaterials to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration. For example, aformulation intended for the oral administration to humans mayconveniently contain from about 0.005 mg to about 2.5 g of active agent,compounded with an appropriate and convenient amount of carriermaterial. Unit dosage forms will generally contain between from about0.005 mg to about 1000 mg of the active ingredient, typically 0.005,0.01 mg, 0.05 mg, 0.25 mg, 1 mg, 5 mg, 25 mg, 50 mg, 100 mg, 200 mg, 300mg, 400 mg, 500 mg, 600 mg, 800 mg or 1000 mg, administered once, twiceor three times a day.

It will be understood, however, that the specific dose level andfrequency of dosage for any particular patient may be varied and willdepend upon a variety of factors including the activity of the specificcompound employed, the metabolic stability and length of action of thatcompound, the age, body weight, general health, sex, diet, mode and timeof administration, rate of excretion, drug combination, the severity ofthe particular condition, and the host undergoing therapy.

Several methods for preparing the compounds of this invention areillustrated in the schemes and examples herein. Starting materials aremade according to procedures known in the art or as illustrated herein.The following examples are provided so that the invention might be morefully understood. The present invention also provides a method for thesynthesis of compounds useful as intermediates in the preparation ofcompounds of the invention.

A general synthesis, is shown in Scheme 1. Treatment of2-methyl-1-nitronaphthalene 1 with Bredereck's reagent affords compound2. Alternatively, compound 1 may be treated with DMF DMA to afford 2.Oxidation of 2 with a reagent like potassium permanganate followed byesterification using anhydrous methanol saturated with HCl affords ester3. Instead of use of anhydrous methanol, the reaction may occur in thepresence of t-BuOH/H₂O, which would yield the free carboxylic acidanalog of 3. Reduction of the nitro group of 3 or its carboxylic acidanalog via a catalyst such as palladium on carbon under an atmosphere ofhydrogen, followed by bromination with bromine would afford 4 (or S inthe case of the carboxylic acid analog). Hydrolysis of 4 using a basesuch as lithium hydroxide affords acid 5. Amide bond formation with(1S,2S)-2-hydroxy-aminocyclohexane using a coupling reagent such as BOP(Benzotriazolyloxytris (dimethylamino)phosphonium hexafluorophosphate)affords 6. Cyclization of 6 to benzoquinazolinone 7 is mediated bydimethylformamide dimethylacetal. Finally, Negishi cross coupling of 7with the appropriate zinc reagent using a catalyst such asbis(tri-tert-butylphosphine)palladium in a solvent like THF affordsExample 70. This may further be functionalized via an additional Negishicoupling with methylzinc chloride to provide Example 2. The Negishicoupling may occur in the presence of Pd(dppf)Cl₂, or in the presence ofPd(Pt-Bu₃)₂ and THF.

As shown in Scheme 2, Example 70 may be transformed into a number ofother examples. Displacement of the chloride with a nucleophile such assodium thiomethoxide in a solvent like DMSO or DMF at elevatedtemperature affords Example 103. Additional oxidation of Example 103 canbe carried out using and oxidant such as 3-chloroperoxybenzoic acid in asolvent like dichloromethane to afford Example 8.

Additionally, as shown in Scheme 3, Example 70 may undergo a Suzuki-typecross coupling with a suitable boron reagent such as 8, in the presenceof a base like cesium carbonate, a transition metal-ligand complex suchas bis(tri-tert-butylphosphine)lpalladium in a solvent like THF toafford Example 5.

As can be seen in Scheme 4, copper catalyzed N-arylation can be effectedwith Example 70 using a heterocycle such as pyrazole, a ligand such astrans-N,N′-dimethylcyclohexane-1,2-diamine, a base like cesiumcarbonate, and copper iodide in a suitable solvent like DMSO to affordExample 6. Similarly, Example 9 may be prepared by using methanol inplace of pyrazole.

Other transition metals may be used in the cross-coupling. In Scheme 5,a zinc reagent such as zinc cyanide, a transition metal catalyst/ligandsuch as bis(tri-tert-butylphosphine)palladium(0), in a solvent like DMFtransforms Example 70 in Example 7.

In Scheme 6, intermediate 9 may be protected as Boc group using areagent like di-tert-butyl dicarbonate to afford 10. Cyclization of 10is mediated by dimethylformamide dimethylacetal followed by Negishicoupling described in Example 70 to afford Example 121. The Boc group ofExample 121 may be removed using a strong acid such as hydrogen chlorideto afford Example 122. Further derivatization of Example 122 such asacylation, may be carried out using acetic anhydride and a base such astriethylamine to afford Example 12.

In Scheme 7, bromide 4 may be converted to boronate 11 using a boronreagent such as pinacol diboron ester, a base like potassium acetate, atransition metal/ligand complex such as[1,1′-bis-(diphenylphosphino)ferrocene]dichloro-palladium( II), 1:1complex with DCM in a solvent like toluene. Suzuki coupling of 11 with ahalide such as 2-(bromomethyl)pyridine hydrobromide, a transitionmetal/ligand complex such as tetrakis(triphenylphosphine)palladium, abase like sodium carbonate in solvents such as toluene and ethanolaffords Example 18.

The following examples are provided to illustrate the invention and arenot to be construed as limiting the scope of the invention in anymanner.

EXAMPLE 1rac-3-[trans-2-hydroxycyclohexyl]-6-[(6-methylpyridin-3-yl)methyl]benzo[h]quinazolin-4(3H)-one

A solution of 2-methyl-1-nitronaphthalane (5.00 g, 26.7 mmol) andtert-butoxybis(dimethylamino)methane (8.27 g, 40.1 mmol) in 10 mL oftoluene was refluxed at 120° C. for 15 h. Additionaltert-butoxybis(dimethylamino)methane (3.76 g, 13.4 mmol) was added andthe reaction was refluxed at 120° C. for another 24 h. The mixture wascooled to rt and 50 mL of hexanes was added. After vigorously stirringfor 30 min, a brick red solid was collected, washed with additionalhexanes, and dried to provide(E)-N,N-dimethyl-2-(1-nitro-2-naphthyl)ethylenamine that gave proton NMRspectra consistent with theory.

To a solution of the above compound (10.0 g, 41.3 mmol) and potassiumcarbonate (13.7 g. 99.0 mmol) in 300 mL of 1:1 t-BuOH:H₂O was addedpotassium permanganate (15.7 g, 99.0 mmol) slowly over 30 min. Thereaction mixture was stirred at rt for 17 h, and a black precipitate wasfiltered and washed twice with 100 mL of water. The filtrate wasconcentrated to 200 mL in volume, and acidified with 6 N HCl to pH˜2. Abeige precipitate was collected, washed twice with 100 mL of water, anddried to provide 1-nitro-2-naphthoic acid that gave proton NMR spectraconsistent with theory and a mass ion (ES+) of 218.1 for [M+H]⁺.

A solution of the above compound (32.5 g, 150 mmol) in 150 mL of MeOHwas cooled to 0° C. and saturated with gaseous HCl. The solution waswarmed to rt and then heated at 90° C. for 22 h. The solution was againsaturated with HCl(g), heated at 90° C. for 20 h, then cooled to rt. Thebeige precipitate was collected, washed with water and MeOH, and driedto provide methyl 1-nitro-2-naphthoate that gave proton NMR spectraconsistent with theory.

To a solution of the above compound (10.0 g, 43.3 mmol) in 250 mL ofMeOH and 3 mL of THF was added palladium on carbon (10 mol %). Thereaction was placed under an atmosphere of hydrogen (1 atm) for 14 h.The mixture was filtered, the solids were washed with additional MeOHand the filtrate was concentrated in vacuo. The residue was concentratedtwice with toluene and dried in vacuo to provide methyl1-amino-2-naphthoate that gave a mass ion (ES+) of 202.1 for [M+H]⁺.

To a solution of the above compound (8.70 g. 43.2 mmol) in 200 ml of 1:1dioxane:CCl₄ at 0° C. was added a solution of bromine (2.23 mL, 43.2mmol) in 40 mL of 1:1 dioxane; CCl₄ dropwise. The mixture was stirred at0° C. for 2 h, filtered and washed with Et₂O, and dried to providemethyl 1-amino-4-bromo-2-naphthoate hydrobromide that gave proton NMRspectra consistent with theory.

A solution of the above compound (3.20 g, 8.86 mmol) inN,N-dimethylformamide dimethylacetal (3.56 mL, 26.6 mmol) was heated at100° C. for 2 h. Additional N,N-dimethylformamide dimethylacetal (1.19mL, 8.9 mmol) was added and the solution was heated at 100° C. for anadditional 3 h. The reaction was cooled to rt. concentrated, and driedto provide crude methyl4-bromo-1-{[(1E)-(dimethylamino)methylene]amino}-2-naphthoate that gavea mass ion (ES+) of 337.1 (⁸¹Br) for [M+H]⁺.

A solution of the above compound (2.20 g, 6.56 mmol) ammonium acetate(0.607 g, 7.88 mmol) in 10 mL of acetic acid was heated at 140° C. for 3h. The reaction was cooled to rt, diluted with 50 mL of water, filtered,washed with water and Et₂O, and dried on high vac to provide6-bromobenzo[h]quinazolin-4(3H)-one that gave a mass ion(ES+) of 276.9(⁸¹Br) for [M+H]⁺.

To a round bottom flask containing the above compound (1.00 g, 3.64mmol) under an atmoshpere of nitrogen was added(2-chloro-5-pyridyl)methylzinc chloride (21.8 mL, 0.5 M in THF, 10.9mmol) and tetrakis(triphenylphosphine)lpalladium(0) (10 mol %).Alternatively, bis(tri-t-butylphospbine)palladium could be used. Thereaction was heated at 90° C. for 7 h. cooled to rt, and diluted with 50mL of ethyl acetate and 50 mL of water. A beige solid was removed viafiltration and the filtrate was washed with brine, dried over sodiumsulfate, filtered, and concentrated in vacuo. The resultant residue waswashed with dichloromethane and dried in vacuo to provide6-[(6-chloropyridin-3-yl)methyl]benzo[h]quinazolin-4(3H)-one that gaveproton NMR spectra consistent with theory and a mass ion (ES+) of 322.0for [M+H]⁺.

To a solution of the above compound (0.400 g, 1.24 mmol) in 5 mL of DMFwas added potassium carbonate (0.344 g. 2.49 mmol) and cyclohexene oxide(0.366 g. 3.73 mmol). The reaction was heated to 120° C. in a sealedpressure vessel for 15 h, and cooled to rt, and diluted with ethylacetate and water. The mixture was partitioned and the organic extractwas washed with brine, dried over sodium sulfate, filtered, andconcentrated in vacuo. The resultant residue was purified via silica gelchromatography, eluting with 10-50% ethyl acetate in hexanes, to providerac-6-[(6-chloropyridin-3-yl)methyl]-3-[trans-2-hydroxycyclohexyl]benzo[h]quinazolin-4(3H)-onethat gave proton NMR spectra consistent with theory and a mass ion (ES+)of 419.9 for [M+H]⁺: ¹H NMR (400 MHz, d₆-DMSO) δ 9.00 (d, J=7.7 Hz, 1H),8.66 (s, 1H), 8.44 (d, J=2.4 Hz, 1H), 8.17 (d, J=7.6 Hz, 1H), 7.97 (s,1H), 7.80-7.73 (m, 2H), 7.68-7.65 (m, 1H), 7.41 (d, J=8.3 Hz, 1H), 4.58(s, 2H), 2.07-204 (m, 2H), 1.89-1.85 (m, 2H), 1.78-1.72 (m, 3H),1.40-1.35 (m, 3H).

To a solution of the above compound (0.225 g, 0.536 mmol) in 5 mL of THFunder an atmosphere of nitrogen was added methyl zinc chloride (0.536mL, 2 M in THF, 1.07 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), 1:1 complexwith DCM (10 mol %). The reaction was heated at 90° C. for 3 h, andadditional methyl zinc chloride (0.536 mL, 2 M in THF, 1.07 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), 1:1 complexwith DCM (5 mol %) were added. The mixture was heated at 100° C. for 15h, cooled to rt, and diluted with ethyl acetate and water. A beige solidwas removed via filtration and the organic layer of the filtrate waswashed with water and brine, dried over sodium sulfate, filtered, andconcentrated in vacuo. The residue was purified via silica gelchromatography, eluting with 20-100% ethyl acetate in hexanes, toprovide the title compound that gave proton NMR spectra consistent withtheory and a mass ion (ES+) of 400.0 for [M+H]⁺: ¹H NMR (400 MHz, CDCl₃)δ 9.02-8.99 (m, 1H), 8.46 (s, 1H), 8.29 (s, 1H), 7.99 (s, 1H), 7.95-7.76(m, 1H), 7.68-7.63 (m, 2H), 7.28-7.17 (m, 1H), 6.98 (d, J=8.0 Hz, 1H),4.63 (brs, 1H), 4.47 (s, 2H), 4.11 (br s, 1 H), 2.49 (s, 3H), 2.29-2.20(m, 1H), 1.95-1.90 (m, 3H), 1.65-1.39 (m, 5H).

EXAMPLE 2 3-[(1S,2S)-2-hydroxycyclohexyl]-6-[(6-methylpyridin-3-yl)methyl]benzo[h]quinazolin-4(3H)-one

Methyl 1-amino-4-bromo-2-naphthoate hydrobromide was prepared asdescribed in Example 1. To a solution of methyl 1amino-4-bromo-2-naphthoate hydrobromide (2.00 g, 5.54 mmol) in 20 mL ofTHF was added sodium hydroxide (11.1 mL, 20% aqueous, 55.4 mmol).Alternatively, lithium hydroxide could be used. The mixture was stirredat 50° C. for 20 h, then heated at 90° C. for 2 h. The solvent wasremoved in vacuo and hydrochloric acid (1 N aqueous) was added until pH˜2. The beige solid was collected via filtration, washed twice withwater, and dried to provide 1-amino-4-bromo-2-naphthoic acid that gave amass ion (ES+) of 266.0 (⁷⁹Br) for [M+H]⁺.

To a solution of the above compound (0.950 g. 3.57 mmol) in 5 mL ofdichloromethane was added(1H-1,2,3-benzotriazol-1-yloxy)[tris(dimethylamino)]phosphoniumhexafluorophosphate (1.82 g, 4.12 mmol), (1S, 2S)-2-aminocyclohexanol(0.493 g, 4.28 mmol), and triethylamine (0.99 mL, 7.1 mmol). The mixturewas stirred at rt for 15 h and then diluted with dichloromethane andwater. The resultant beige solid was collected via filtration, washedwith dichloromethane and water, and dried to provide1-amino-4-bromo-N-[(1S,2S)-2-hydroxycyclohexyl]-2-naphthamide that gavea mass ion (ES+) of 364.9 (⁸¹Br) for [M+H]⁺. A solution of the abovecompound in N,N-dimethylformamide dimethylacetal (3.06 mL, 22.8 mmol)was heated at 80° C. for 15 h. The reaction was cooled to rt,concentrated in vacuo, and dried to provide6-bromo-3-[(1S,2S)-2-hydroxycyclohexyl]benzo[h]quinazolin-4(3H)-one thatgave a mass ion (ES+) of 374.8 (⁸¹Br) for [M+H]⁺.

The titled compound was prepared by employing the procedures describedin Example 1 that gave proton NMR spectra consistent with theory and amass ion(ES+) of 400.0 for [M+H]⁺; ¹H NMR (400 MHz, CDCl₃) δ 9.00-8.99(m, 1H), 8.45 (s, 1H), 8.29 (s, 1H), 7.95 (s, 1H), 7.95-7.76 (m, 1H),7.68-7.63 (m, 2H), 7.27-7.17 (m, 1H), 6.96 (d, J=8.0 Hz, 1H), 4.62 (brs, 1H), 4,35 (s, 2H), 4.11 (brs, 1H), 2.48 (s, 3H), 2.29-2.20 (m, 1H),1.95-1.90 (m,3H), 1.65-1.39 (m, 5H).

EXAMPLE 36-(4-methoxybenzyl)-3-(5-methyl)-1H-pyrazol-3-yl)benzo[h]quinazolin-4(3H)-one

Methyl 1-amino-4-bromo-2-naphthoate hydrobromide was prepared asdescribed in Example 1. To a round bottom flask containing methyl1-amino-4-bromo-2-naphthoate hydrobromide (3.50 g, 9.69 mmol) under anatmosphere of nitrogen was added 4-metboxybenzylzinc chloride (97.0 mL,0.5 M in THF, 48.5 mmol) and tetrakis(triphenylphosphine)palladium(0)(10 mol %). The mixture was heated at 90° C. for 7 h, cooled to rt, anddiluted with 50 mL of ethyl acetate and 50 mL of water. The mixture waspartitioned and the organic extract was washed with brine, dried oversodium sulfate, filtered, and concentrated in vacuo. The residue waspurified via silica gel chromatography, eluting with 0-20% ethyl acetatein hexanes, to provide methyl 1-amino-4-(4-methoxybenzyl)-2-naphthoatethat gave proton NMR spectra consistent with theory and a mass ion (ES+)of 322.0 for [M+H]⁺.

A solution of the above prepared compound (1.41 g, 4.39 mmol) inN,N-dimethylformamide dimethylacetal (1.76 mL, 13.2 mmol) was heated at100° C. for 4 h. Additional N,N-dimethylformamide dimethylacetal (0.44mL, 3.3 mmol) was added and the solution was heated at 100° C. for 1 h.The mixture was cooled to rt. concentrated in vacuo to provide methyl1-{[(1E)-(dimethylamino)methylene]amino}-4-(4-methoxybenzyl)-2-naphthoatethat gave a mass ion (ES+)of 377.0 for [M+H]⁺.

To a solution of the above prepared compound (0.040 g, 1.1 mmol) in 0.5mL of acetic acid was added 3-amino-5-methylpyrazole (10.7 mg, 1.10mmol). The mixture was heated at 100° C. for 6 h and then cooled to rtand concentrated in vacuo. The residue was purified via preparativereverse phase HPLC to provide the title compound that gave a mass ion(ES+) of 433.1653 for [M+H]⁺.

EXAMPLE 4 6-(4-methoxybenzyl)-3-pyridin-3-ylbenzo[h]quinazolin-4(3H)-one

6-(4-methoxybenzyl)benzo[h]quinazolin-4(3H)-one was prepared by the sameprocedure as described for6-[(6-chloropyridin-3-yl)methyl]benzo[h]quinazolin-4(3H)-one inExample 1. To a solution of6-(4-methoxybenzyl)benzo[h]quinazolin-4(3H)-one (0.030 g, 0.095 mmol)and 3-iodopyridine (0.058 g, 0.28 mmol) in 2 mL of THE and 1 mL of DMSOunder an atmosphere of nitrogen was added cesium carbonate (0.19 mL, 1 Naqueous, 0.19 mmol), trans-N,N′-dimethylcyclohexane-1,2-diamine (1.3 mg.0.0095 mmol), and copper(I) iodide (1.8 mg, 0.095 mmol). The reactionwas heated at 120° C. for 15 h, cooled to rt, and concentrated in vacuo.The residue was purified via preparative reverse phase HPLC to providethe title compound that gave a proton NMR spectra consistent with theoryand a mass ion (ES+) of 393.9 for [M+H]⁺: ¹H NMR (400 MHz, d6-DMSO) δ9.07 (d, J=8.0, 1H), 8.53 (s, 1H), 8.42 (s, 1H), 8.14 (d, J=7.6 Hz, 1H),8.07 (d, J=9.6 Hz, 2H), 7.95 (s, 1H), 7.74-7.54 (m, 5H), 4.57 (s, 2H),4.21-4.09 (m, 1H), 3.92 (s, 3H), 2.20-2.18 (m, 1H), 2.03-1.96 (m, 1H),1.95-183 (m, 2H), 158-1.39 (m, 3H), 1.29-1.18 (m, 2H).

EXAMPLE 5rac-3-[trans-2-hydroxycyclohexyl]-6-{[6-(1-methyl-1H-pyrazol-4-yl)pyridine-3-yl]methyl}benzo[h]quinazolin-4(3H)-one

rac-6-[(6-chloropyridin-3-yl)methyl]-3-[trans-2-hydroxycyclohexyl]benzo[h]quinazolin-4(3H)-onewas prepared as described in Example 1.

To a solutionrac-6-[(6-chloropyridin-3-yl)methyl]-3-[trans-2-hydroxycyclohexyl]benzo[h]quinazolin4(3H) one (0.080) g, 0.19 mmol) in 3 mL of THF under an atmosphere ofnitrogen was added cesium carbonate (0.38 mL, 1 N aqueous, 0.38 mmol),1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(0.079 g, 0.38 mmol), and bis(tri-tert-butylphosphine)palladium(0) 110mol %). The reaction was heated at 100° C. for 20 h, cooled to rt, anddiluted with ethyl acetate and water. The organic layer was removed andwashed with saturated aqueous sodium bicarbonate and brine, dried oversodium sulfate, filtered, and concentrated in vacuo. The residue waspurified via silica gel chromatography, eluting with 100% ethyl acetate,to provide the title compound that gave a proton NMR spectra consistentwith theory and a mass ion (ES+)H of 466.0 for [M+H]⁺: ¹H NMR (400 MHz,CD₃OD) δ 9.02-8.99 (m, 1H), 8.67 (br s, 1H), 8.61 (s, 1H), 8.33 (s, 1H),8.23 (d, J=7.5 Hz, 1H), 8.03-8.00 (m, 2H), 7.82-7.62 (m, 4H), 4.60 (s,2H), 4.10-4.04 (m, 1H), 3.89 (s, 3H), 2.08-2.00 (m, 1H), 1.93-1.83 (m,1H), 1.90-1.72 (m, 3H), 1.38-1.30 (m, 4H).

EXAMPLE 6rac-3-[trans-2-hydroxycyclohexyl]-6-{[6-(1H-pyrazol-1-yl)pyridin-3-yl]methyl}benzo[h]quinazolin-4(3H)-one

To a solutionrac-6-[(6-chloropyridin-3-yl)methyl]-3-[trans-2-hydroxycyclohexyl]benzo[h]quinazolin-4(3H)-one(0.050 g. 0.12 mmol) and pyrazole (0.024 g, 0.36 mmol) in 2 mL of DMSOunder an atmosphere of nitrogen was added cesium carbonate (0.24 mL, 1 Naqueous, 0.24 mmol), trans-N,N′-dimethylcyclohexane-1,2-diamine (1.7 mg,0.012 mmol), and copper(1) iodide (2.3 mg, 0.012 mmol). The mixture washeated at 130° C. for 24 h,, cooled to rt, and purified via preparativereverse phase HPLC. The appropriate fractions were concentrated invacuo. The residue was taken up in saturated aqueous sodium bicarbonateand extracted 3 times with ethyl acetate. The combined organic extractswere washed with brine, dried over sodium sulfate, filtered, andconcentrated in vacuo to provide the title compound that gave a protonNMR spectra consistent with theory and a mass ion (ES+) of 452.0 for[M+H]⁺: ¹H NMR (400 MHz, CDCl₃) δ 9.01-8.99 (m, 1H), 8.50 (s, 1H),8.32-8.30 (m, 2H), 8.02 (s, 1H), 7.93-7.91 (m, 1H), 7.84 (d, J=8.2 Hz,1H), 7.69-7.64 (m, 3H), 7.56 (d, J=8.4 Hz, 1H), 6.43 (s, 2H), 4.63 (brs, 1H), 409 (br s, 1H), 2.28-2.22 (m, 1H), 2.14-2.00 (m, 1H), 1.94-1.84(m, 3H), 1.60-140 (m, 3H), 1.18-1.10 (m, 1H).

EXAMPLE 7rac-5-({3-[trans-2-hydroxycyclohexyl]-4-oxo-3,4-dihydrobenzo[h]quinazolin-6yl}methyl)pyridine-2-carbonitrile

To a solutionrac-6-[(6-chloropyridin-3-yl)methyl]-3-[trans-2-hydroxycyclohexyl]benzo[h]quinazolin-4(3H)-one(0.050 g, 0.12 mmol) and zinc cyanide (0.042 g, 0.36 mmol) in 2 mL ofDMF under an atmosphere of nitrogen was addedbis(tri-tert-butylphosphine)palladium(0) (10 mol %). The mixture wasirradiated in a microwave reactor at 160° C. for 1 h, cooled to rt,filtered, and purified via preparative reverse phase HPLC to provide thetitle compound that gave a proton NMR spectra consistent with theory anda mass ion (ES+) of 411.0 for [M+H]⁺: ¹H NMR (400 MHz, CDCl₃) δ9.04-9.02 (m, 1H),8.70 (s, 1H), 8.46 (s, 1H), 8.06 (s, 1H), 7.84-7.80(m, 1H), 7.76-7.64 (m, 2H), 7.57-7.52 (m, 2H), 4.67 (br s, 1H), 4.55 (s,2H), 4.02 (br s, 1H), 2.30-2.22 (m, 1H). 2.10-2.03 (m, 1H), 2.00-1.83(m, 3H), 1.59-1.21 (m, 3H).

EXAMPLE 8rac-3-[trans-2-hydroxycyclohexyl]-6-{[6-methylsulfonyl)pyridine-3-yl]methyl}benzo[h]quinazolin-4(3H)-one

A solution ofrac-6-[(6-chloropyridin-3-yl)methyl]-3-[trans-2-hydroxycyclohexyl]benzo[h]quinazolin-4(3H)-one(0.150 g, 0.357 mmol) and sodium thiomethoxide (0.075 g, 1.1 mmol) in 2mL of DMF was healed at 120° C. for 15 h, cooled to rt and diluted withethyl acetate. The organic solution was washed with water and brine,dried over sodium sulfate, filtered, and concentrated in vacuo. Theresidue was purified via silica gel chromatography, eluting with 0-50%ethyl acetate in hexanes, to provide the title compound that gave aproton NMR spectra consistent with theory and a mass ion (ES+) of 432.0for [M+H]⁺: ¹H NMR (400 MHz, CDCl₃) δ 8.98 (d, J=5.6 Hz, 1H), 8.38 (s,1H), 8.28 (s, 1H), 7.98 (s, 1H), 7.92-7.89 (m, 1H), 7.67-7.63 (m, 2H),7.26-7.22 (m, 2H), 7.04-7.02 (m, 1H), 4.63 (br s, 1H), 435 (s, 2H), 4.04(br s, 1H), 2.52 (s, 3H), 150-2.43 (m, 1H), 230-2.22 (m, 1H), 2.00-1.83(m, 3H), 1.59-1.43 (m, 3H).

To a solution of the above prepared compound (0.045 g, 0.10 mmol) in 3mL of dichloromethane at 0° C. was added 3-chloroperoxybenzoic acid(0.045 g. 0.26 mmol). The mixture was warmed to rt, stirred for 2 h andthen purified via silica gel chromatography, eluting with 20-70% ethylacetate in hexanes, to provide the title compound that gave a proton NMRspectra consistent with theory and a mass ion (ES+) of 463.8 for [M+H]⁺:¹H NMR (400 MHz, CDCl₃) δ 9.05-9.03 (m, 1H), 8.67 (s, 1H), 8.32 (s, 1H),8.04 (s, 1H), 7.97-7.92 (m, 2H), 7.84-7.81 (m, 1H). 7.72-7.66 (m, 3H),4.65 (br s, 1H), 4.55 (s, 2H), 4.03 (br s, 1H), 3.20 (s, 3H), 2.30-2.23(m, 1H), 2.00-1.83 (m, 3H), 1.61-1.43 (m, 4H).

EXAMPLE 9rac-3-[trans-2-hydroxycyclohexyl]-6-[(6-methoxypyridin-3-yl)methyl]benzo[h]quinazolin-4(3H)-one

A solution ofrac-6-[(6-chloropyridin-3-yl)methyl]-3-[trans-2-hydroxycyclohexyl]benzo[h]quinazolin-4(3H)-one(0.150 g, 0.357 mmol) in 3 mL of MeOH under an atmosphere of nitrogenwas added trans-N,N′-dimethylcyclohexane-1,2-diamine (1.7 mg, 0.012mmol), and cupper(I) iodide (2.3 mg, 0.012 mmol). The mixture wasirradiated in a microwave reactor at 160° C. for 4 h, cooled to it andconcentrated in vacuo. The residue was purified via silica gelchromatography, eluting with 0-100% ethyl acetate in hexanes, to providethe title compound that gave a proton NMR spectra consistent with theoryand a mass ion (ES+) of 416.0 for [M+H]⁺: ¹HNMR (400 MHz, CDCl₃) δ9.03-8.99 (m, 1H), 8.29 (s, 1H), 8.10 (s, 1H), 8.02-7.99 (m, 2H),7.70-7.65 (m, 2H), 737-734 (m, 1H), 6.62 (d, J=8.5 Hz, 1H), 4.82 (br s,1H), 4.39 (s, 2H), 4.01 (br s, 1H), 3.90 (s, 3H), 2.30-2.23 (m, 1H),2.18-2.12 (m, 1H), 1.99-1.84 (m, 3H), 1.53-1-42 (m, 3H).

EXAMPLE 106-[(6-chloropyridin-3-yl)methyl]-3-(2-oxycyclohexyl)benzo[h]quinazolin-4(3H)-one

To a solution ofrac-6-[(6-chloropyridin-3-yl)methyl]-3-[trans-2-hydroxycyclohexyl]benzo[h]quinazolin-4(3H)-one(0.050 g, 0.12 mmol) in 3 mL of dichloromethane containing powdered 4 Åmolecular sieves was added 4-methylmorpholine 4-oxide (0.018 g, 0.16mmol). After 15 min, tetrabutylammonium perruthenate (0.013 g, 0.036mmol) was added and after 30 min, the mixture was filtered through a padof Celtie. The filtrate was concentrated in vacuo and purified viapreparative reverse phase HPLC to provide the title compound that gave aproton NMR spectra consistent with theory and a mass ion (ES+) of 417.9for [M+H]⁺: ¹H NMR (400 MHz,CDCl₃) δ 9.03-9.00 (m, 1H), 8.60 (s, 1H),8.49 (s, 1H), 7.96-7.93 (m, 1), 7.81-7.76 (m, 2H), 7.55-7.48 (m, 1H),7.29-7.26 (m, 1H), 5.78-5.73 (m, 1H), 4.53 (s, 2H), 2.80-2.71 (m, 1H),2.66-2.58 (m, 1H), 2.51-2.47 (m, 1H), 2.30-2.18 (m, 3H), 2.06-1.83 (m,2H).

EXAMPLE 11trans-2-[6-[(6-chloropyridin-3-yl)methyl]-4-oxycyclohexyl[h]quinazolin-3(4yl]cyclohexylrac-acetate

To a solution ofrac-6-[(6-chloropyridin-3-yl)methyl]-3-[trans-2-hydroxycyclohexyl]benzo[h]quinazolin-4(3H)-one(0.040 g, 0.095 mmol) in 2 mL of CH₂Cl₂ at 0° C. was added aceticanhydride (0.011 ml, 0.11 mmol) and triethylamine (0.026 mL, 0.20 mmol).The mixture was warmed to rt and after 15 h, concentrated in vacuo. Theresidue was purified via preparative reverse phase HPLC to provide thetitle compound that gave a proton NMR spectra consistent with theory anda mass ion(ES+) of 461.9 for [M+H]⁺.

EXAMPLE 12N-{1S,2S)-2-[6-[(6-chloropyridin-3-yl)methyl]-4-oxobenzo[h]quinazolin-3(4H)-yl]cyclohexyl}acetamide

1-Amino-N-[(1S,2S)-2-aminocyclohexyl]-4-bromo-2-naphthamide was preparedby the procedure described for the synthesis of1-amino-4-bromo-N-[(1S,2S)-2-hydroxycyclohexyl]-2-naphthamide in Example1.

To a solution of1-amino-N-[(1S,2S)-2-aminocyclohexyl]-4-bromo-2-naphthamide (0.460 g,1.27 mmol) in 20 mL of dichloromethane was added di-tert-butyldicarbonate (0.305 g, 1.40 mmol). The mixture was stirred at rt for 4 hand then purified via silica gel chromatography, eluting with 0-20%ethyl acetate in hexanes, to provide tert-butyl{(1S,2S)-2-2[(1-amino-4-bromo-2-naphthoyl)amino]cyclohexyl)carbamatethat gave a mass ion (ES+) of 463.9 for [M+H]⁺.

The above prepared compound was converted to provide tert-butyl{(1S,2S)-2-[6-[(6-chloropyridin-3-yl)methyl]-4-oxobenzo[h]quinazolin-3(4H)-yl]cyclohexyl}carbamateby the procedure described for the synthesis of6-[(6-chloropyridin-3-yl)methyl]-3-[(1S,2S)-2-hydroxylcyclohexyl]benzo[h]quinazolin-4(3H)-onein Example 2.

To a solution of tert-butyl{(1S,2S)-2-[6-[6-chloropyridin-3-yl)methyl]-4-oxoenzo[h]quinazolin-3(4H)-yl]cyclohexyl}carbamate(0.080 g, 0.15 mmol) in 2 mL of methanol was added hydrochloric acid(0.15 mL, 6 N aqueous, 0.92 mmol). The reaction was heated at 60° C. for2 h, cooled to ambient temperature and concentrated in vacuo. Theresidue was concentrated twice with toluene. The residue was purifiedvia preparative reverse phase HPLC to provide3-[(1S,2S)-2-aminocyclohexyl]-6-[(6-chloropyridin-3-yl)methyl]benzo[h]quinazolin-4(3H)-onethat gave a proton NMR spectra consistent with theory and a mass ion(ES+) of 419.0 for [M+H]⁺: ¹H NMR (400 MHz, d₆-DMSO) δ 9.10-9.08 (m,1H), 8.56 (br s, 1H), 8.27 (s, 1H), 8.14-8.12 (m, 1H). 8.04 (s, 1H),7.80-7.75 (m, 3H), 7.43-7.36 (m, 1H), 4.60 (s, 2H), 2.31-2.24 (m, 2H),2.12-1.94 (m, 4H), 1.70-1.56 (m, 4H).

To a solution of the above prepared compound (0.025 g, 0.055 mmol) in 2mL of dichloromethane at 0° C. was added triethylamine (0.023 mL, 0.16mmol) and acetic anhydride (0.0078 mL, 0.082 mmol). The mixture wasstirred at 0° C. for 2 h, diluted with dichloromethane and washed withwater and brine, dried over sodium sulfate, filtered, and concentratedin vacuo. The residue was purified via silica gel chromatography,eluting with 10-100% ethyl acetate in hexanes, to provide the titlecompound that gave a proton NMR spectra consistent with theory and amass ion (ES+) of 460.9 for [M+H]⁺: ¹H NMR (400 MHz, CDCl₃) δ 9.11-9.08(m, 1H), 8.38 (s, 1H), 8.02 (s, 1H), 7.93-7.91 (m, 1H), 7.72-7.68 (m,2H), 7.41-7.39 (m, 1H), 7.20-7.17 (m, 1H), 5.76-5.74 (m, 1H), 4.94-4.88(m, 1H), 4.47 (s, 2H), 4.29-4.24 (m, 1H), 2.28-2.21 (m, 1H), 2.16-2.02(m, 1H), 2.00-1.82 (m, 3H) 1.72 (s, 3H), 1.60-1.41 (m, 3H).

EXAMPLE 133-[(1S,2S)-2-hydroxycyclohexyl]-6-[(6-isopropylpyridin-3-yl)methylbenzo[h]quinazolin-4(3H)-one

To a solution ofrac-6-[(6-chloropyridin-3-yl)methyl]-3-[trans-2-hydroxycyclohexyl]benzo[h]quinazolin-4(3H)-one(0.250 g, 0.595 mmol) in 3 mL of THF and 0.5 mL of water under anatmosphere of nitrogen was added potassium carbonate (0.091 g, 0.66mmol), isopropenylboronic acid pinacol ester (0.200 g, 1.19 mmol), and[1,1′-bis(diphenyl-phosphino)ferrocene]dichloropalladium(II), 1:1complex with DMC (10 mol %) (0.022 g, 0.030 mmol). The mixture washeated at 100° C. for 18 h, cooled to rt, and diluted with ethyl acetateand water. The mixture was partitioned and the organic layer was washedwith saturated aqueous sodium bicarbonate and brine, dried over sodiumsulfate, filtered, and concentrated in vacuo. The residue was purifiedvia silica gel chromatography, eluting with 10-50% ethyl acetate inhexanes, to provide3-[(1S,2S)-2-hydroxycyclohexyl]-6-[(6-isopropenylpyridin-3-yl)methylbenzo[h]quinazolin-4(3H)-onethat gave a proton NMR spectra consistent with theory and a mass ion(ES+) of 426.0 for [M+H]⁺: ¹H NMR (400 MHz, CDCl₃) δ 9.05-9.03 (m, 1H),8.57 (s, 1H), 8.30 (s, 1H), 8.09 (s, 1H), 8.00-7.97 (m, 1H), 7.69-7.66(m, 2H), 7.39-7.33 (m, 2H), 5.80 (s, 1H), 5.25(s, 1H), 4.72-4.60 (m,1H), 4.49 (s, 2H), 4.05-3.97 (m, 1H), 2.30-2.23 (m, 1H), 2.18 (s, 3H),2.12-2.02 (m, 1H), 1.99-1.92 (m, 3H), 1.58-1.44 (m, 3H).

To a solution of the above compound (0.030 g, 0.71 mmol) in 3 mL of MeOHwas added palladium on carbon (110 mol %). The mixture was placed underan atmosphere of hydrogen (1 atm) for 3 h and was then filtered througha pad of Celite, which was washed with MeOH. The filtrate wasconcentrated in vacuo to provide the title compound that gave a protonNMR spectra consistent with theory and a mass ion (ES+)H of 428.0 for[M+H]⁺: ¹H NMR (400 MHz, CDCl₃) δ 9.04-9.00 (m, 1H), 8.52 (s, 1H), 8.30(s, 1H), 8.04 (s, 1H), 8.00-7.96 (m, 1H), 7.69- 7.65 (m, 2H), 7.35-7.31(m, 1H), 7.01 (d, J=8.0 Hz, 1H), 4.72-4.60 (m, 1H), 4.42 (s, 2H),4.04-3.97 (m, 1H), 3.04-2.95 (m, 1H), 2.26-2.20 (m, 1H), 2.09-2.01 (m,1H), 1.99-1.83 (m, 3H), 1.63-1.41 (m, 4H), 1.26 (d, J=6.9 Hz, 6H).

EXAMPLE 143-[(1S,2S)-2-hydroxycyclohexyl]-6-{[(6-(1-hydroxy-1-methylethyl)pyridin-3-yl]methyl}benzo[h]quinazolin-4(3H)-one

3-[(1S,2S)-2-hydroxycyclohexyl]-6-[(6-isopropylpyridin-3-yl)methylbenzo[h]quinazolin-4(3H)-onewas prepared as described in Example 13.

To a solution of3-[(1S,2S)-2-hydroxycyclohexyl]-6-[(6-isopropylpyridin-3-yl)methylbenzo[h]quinazolin-4(3H)-onein 4 mL solution of THF acetone:water (2:1:1) was added sodium periodate(0.075 g, 0.353 mmol), and osmium tetroxide (4 wt % in water, 3 dropsfrom a 9″(pipet) and after 4 h, additional osmium tetroxide (4 wt % inwater, 3 drops from a 9″pipet) was added. After an additional 3 h, themixture was diluted with ethyl acetate, washed with aqueous sodiumthiosulfate and brine, dried over sodium sulfate, filtered, andconcentrated in vacuo. The residue was purified via silica gelchromatography, eluting with 10-50% ethyl acetate in hexanes, to provide6-[(6-acetylpyridin-3-yl)methyl]3-[(1S,2S)-2-hydroxycyclohexyl]benzo[h]quinazolin-4(3H)-onethat gave a proton NMR spectra consistent with theory and a mass ion(ES+) of 428.0 for [M+H]⁺: ¹H NMR (400 MHz, CDCl₃) δ 9.04-9.02 (m, 1H),8.61 (s, 1H), 8.31 (s, 1H), 8.04 (s, 1H), 7.97-7.87 (m, 2H), 7.71-64 (m,2H), 7.57-7.52 (m, 1H), 4.71-4.60 (m, 1H), 4.53 (s, 2H), 4.06-4.00 (m,1H), 2.68(s, 3H), 2.28-2.23 (m, 1H), 2.20-2.17 (m, 1H), 2.00-1.85 (m,3H), 1.60-1.42 (m, 3H).

To a solution of the above prepared compound (0.010 g, 0.023 mmol) in 2mL of dichloromethane at −40° C. was added methylmagnesium bromide(0.016 mL, 3.0 M diethyl ether solution, 0.047 mmol). After 1 h −40° C.,the mixture was treated with saturated aqueous ammonium chloride,concentrated in vacuo, and purified via preparative reverse phase HPLCto provide the title compound that gave a proton NMR spectra consistentwith theory and a mass ion (ES+) of 444.1 for [M+H]⁺: ¹H NMR (400 MHz,CD₃OD) δ 9.12-9.10 (m, 1H), 8.57 (s, 1H), 8.52 (s, 1H), 8.43-3.41 (m,1H), 8.12-8.00 (m, 3H), 7.81-7.73 (m, 2H), 4.86 (s, 2H), 4.21-4.10 (m,1H), 2.22-2.17 (m, 1H), 2.04-1.97 (m, 1H), 1.96-1.81 (m, 2H), 1.63 (s,6H), 1.56-1.43 (m, 3H).

EXAMPLE 15rac-3-[trans-2-hydroxycyclohexyl]-6-{[(6-hydroxymethyl)pyridin-3-yl]methyl}benzo[h]quinazolin-4(3H)-one

Rac-5-({3-[trans-2-hydroxycyclohexyl]-4-oxo-3,4-dihydrobenzo[h]quinazolin-6-yl}methyl)pyridine-2-carbaldehydewas prepared by the same procedure as described for the synthesis of6-[(6-acetylpyridin-3-yl)methyl]-3-[(1S,2S)-2-hydroxycyclohexyl]-benzo[h]quinazolin-4(3H)-onein Example 14.

To a solution ofrac-5-({3-[trans-2-hydroxycyclohexyl]-4-oxo-3,4-dihydrobenzo[h]quinazolin-6-yl}methyl)pyridine-2-carbaldehyde(0.070 g, 0.17 mmol) in 3 mL of MeOH was added sodium borohydride(0.0096 g, 0.25 mmol). After 1 h, the mixture was treated with saturatedaqueous ammonium chloride, concentrated in vacuo, and diluted with ethylacetate. The organic solution was washed with water and brine, driedover sodium sulfate, filtered, and concentrated in vacuo. The residuewas purified via preparative reverse phase HPLC to provide the titlecompound that gave a proton NMR spectra consistent with theory and amass ion (ES+) of 416.0 for [M+H]⁺: ¹H NMR (400 MHz, CD₃OD) δ 9.06-9.04(m, 1H), 8.53 (s, 1H), 8.53 (s, 1H), 8.07 (s, 1H), 8.02-7.95 (m, 1H),7.70-7.67 (m, 1H), 7.46-7.43 (m, 1H), 7.12-7.10 (m, 1H), 4.71 (s, 2H),4.69-4.61 (m, 1H), 4.4 (s, 2H), 4.04-4.00 (m, 1H), 2.28-2.18 (m, 1H),1.94-1.88 (m, 1H), 1.72-1.40 (m, 6H).

EXAMPLE 16Rac-3-[trans-2-hydroxycyclohexyl]-6-[(6-methoxypyridin-3-yl)methyl]benzo[h]quinazolin-4(3H)-one

Rac-3-[trans-2-hydroxycyclohexyl]-6-[(6-methoxypyridin-3-yl)methyl]benzo[h]quinazolin-4(3H)-onewas prepared as described in Example 9.

To a solution ofrac-3-[trans-2-hydroxycyclohexyl]-6-[(6-methoxypyridin-3-yl)methyl]benzo[h]quinazolin-4(3H)-one(0.025 g, 0.060 mmol) in 1 mL of acetontrile in a screw capped via wasadded iodomethane (0.031 g, 0.22 mmol). The vessel was sealed and heatedat 90° C. for 48 h, cooled to rt, and concentrated in vacuo. The residuewas purified via preparative reverse phase HPLC to provide the titlecompound that gave proton NMR spectra consistent with theory and a massion (ES+) of 416.1 for [M+H]⁺: ¹H NMR (400 MHz, CDCl₃) δ 9.07-9.05 (m,1H), 8.41 (s, 1H), 8.06 (s, 1H), 7.94-7.92 (m, 1H), 7.75-7.72 (m, 2H),7.45 (d, J=2.5 Hz, 1H), 7.02 (s,1H), 6.77 (d, J=9.3 Hz, 1H), 4.68 (br s,1H), 4.27 (s, 2H), 4.01 (br s, 1H), 3.50 (s, 3H), 2.28-1..88 (m, 5H),1.59-144 (m, 3H).

EXAMPLE 173-[(1S,2S)-2-hydroxycyclohexyl]-6-[(6-methyl-1-oxidopyridin-3-yl)methyl]benzo[h]quinazolin-4(3H)-one

3-[(1S,2S)-2-hydroxycyclohexyl]-6-[(6-methylpyridin-3-yl)methyl]benzo[h]quinazolin-4(3H)-onewas prepared as described in Example 2.

To a suspension of3-[(1S,2S)-2-hydroxycyclohexyl]-6-[(6-methylpyridin-3-yl)methyl]benzo[h]quinazolin-4(3H)-onehydrochloride (0.050 g, 0.12 mmol) in 0.6 mL of dichloromethane wasadded triethylamine (0.012 g, 0.12 mmol). Upon dissolution of thesuspension, 3-chloroperoxybenzoic acid (0.031 g, 0.13 mmol) was addedand the mixture was stirred at rt for 15 h. The mixture was diluted withdichloromethane, washed with saturated aqueous sodium carbonate, driedover sodium sulfate, filtered, and concentrated in vacuo. The residuewas purified via silica gel chromatography, eluting with 0-10% methanolin dichloromethane, to provide the title compound that gave proton NMRspectra consistent with theory and a mass ion (ES+) of 416.1967 for[M+H]⁺: ¹H NMR (400 MHz, CDCl₃) δ 8.99-8.96 (m, 1H), 8.29 (s, 1H), 8.12(s, 1H), 7.98 (s, 1H), 7.79-7.76 (m, 1H), 7.65-7.59 (m, 2H), 6.92 (d,J=8.1 Hz, was 1H), 4.61 (br s, 1H), 4.31 (s, 2H), 4.00 (br s, 1H),2.50-2.40 (m, 1H), 2.41 (s, 3H), 2.26-2.21 (m, 1H), 2.06-1.98 (m, 1H),1.98-1.82 (m, 3H), 1.58-1.40 (m, 3H).

EXAMPLE 183-[(1S,2S)-2-hydroxycyclohexyl]-6-(pyridin-2-ylmethyl)benzo[h]quinazolin-4(3H)-one

6-bromo-3-[(1S,2S)-2-hydroxycyclohexyl]-benzo[h]quinazolin-4(3H)-one wasprepared as described in Example 2.

To a solution of6-bromo-3-[(1S,2S)-2-hydroxycyclohexyl]-benzo[h]quinazolin-4(3H)-one(0.300 g, 0.804 mmol) in 6.5 mL of toluene was addedbis(pinacolato)diboron (0.225 g, 0.884 mmol), potassium acetate (0.158g, 1.61 mmol), and[1,1′-bis(diphenylphosphino)ferrocene]dichloro-palladium(II), 1:1complex with DCM (0.029 g, 0.040 mmol) under an atmosphere of nitrogen.The mixture was irradiated in a microwave reactor at 150° C. for 90 min,cooled to rt and diluted with ethyl acetate. The organic solution waswashed twice with water, dried over sodium sulfate, filtered, andconcentrated in vacuo. The residue was purified via silica gelchromatography, eluting with 0-50% ethyl acetate in hexanes, to provide3-[(1S,2S)-2-hydroxycyclohexyl]-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[h]quinazolin-4(3H)-onethat gave a mass ion (ES+) of 421.0 for [M+H]⁺.

To a solution of the above prepared compound (0.080 g, 0.190 mmol) in 1mL of toluene and 0.8 mL of ethanol was added 2-(bromomethyl)pyridinehydrobromide (0.048 g, 0.19 mmol), sodium carbonate (0.76 mL, 2 Maqueous, 1.5 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.143g, 0.124 mmol) under an atmosphere of nitrogen. The mixture was heatedat 85° C. for 3 h, cooled to rt and diluted with ethyl acetate. Theorganic solution was washed with aqueous sodium sulfate and brine, driedover sodium sulfate, filtered, and concentrated in vacuo. The residuewas purified via preparative reverse phase HPLC to provide the titlecompound that gave proton NMR spectra consistent with theory and a massion (ES+) of 386.0 for [M+H]⁺: ¹H NMR (400 MHz, CDCl₃) δ 9.06-9.04 (m,1H), 8.92 (d, J=5.1 Hz, 1H), 8.38 (s, 1H), 8.17 (s, 1H), 7.99-7.89 (m,2H), 7.74-7.69 (m, 2H), 7.62-7.58 (m, 1H), 7.26-7.24 (m, 1H), 5.02-4.91(m, 2H), 4.67 (br s, 1H), -4.03 (br s, 1H), 2.33-2.24 (m, 1H), 2.10-2.00(m, 1H), 2.00-1.86 (m, 3H), 1.60-1.43 (m, 3H).

EXAMPLE 196-[(6-chloropyridin-3-yl)methyl]-3-[(1S,2S)-2-hydroxycyclohexyl]-2-methylbenzo[h]quinazolin-4(3H)-one

Using the procedures described in Example 2 for the preparation of6-[(6-chloropyridin-3-yl)methyl]-3-[(1S,2S)-2-hydroxycyclohexyl]benzo[h]quinazolin-4(3H)-one,substituting N,N-dimethylacetamide dimethylacetal forN,N-dimethylformamide dimethylacetal, the title compound was obtainedthat gave proton NMR spectra consistent with theory and a mass ion (ES+)of 433.9 for [M+H]⁺: ¹H NMR (400 MHz, d₆-DMSO) δ 9.05-9.03 (m, 1H), 8.28(s, 1H), 8.06 (d, J=7.7, 1H), 7.92 (s, 1H), 7.75-7.63 (m, 3H), 7.34 (d,J=8.4 Hz, 1H), 4.80-4.74 (m, 1H), 4.53 (s, 2H), 4.15-4.09 (m, 1H), 2.87(s, 3H), 2.81-2.70 (m, 1H), 2.19-2.12 (m, 1H), 1.90-1.80 (m, 3H),1.53-1.35 (m, 3H).

The following compounds of formula (III) above, wherein R³ is hydrogen,are depicted below in Table 1. The Table 1 compounds were preparedaccording to the general procedures provided in Examples 1-20. Thestarting materials are either commercially available of may be preparedfrom commercially available reagents using conventional reactions wellknown in the art.

TABLE 1 Exemplary compounds of FIG. (III), wherein R³ is HydrogenExample No. Stereospecificity R² R⁷ MS Method 20 —

OMe 411.1527 Example 1 21 — H OMe 317.0 Example 1 22 — Allyl OMe 357.0Example 1 23 — Me OMe 331.0 Example 1 24 — Ph OMe 392.9 Example 4 25racemic

OMe 414.9 Example 1 26 — 3-pyridyl OMe 393.9 Example 4 27 — 4-pyridylOMe 393.9 Example 4 28 —

OMe 407.0 Example 1 29 —

OMe 373.0 Example 1 30 — CH₂CH₂CN OMe 369.94 Example 1 31 —

OMe 400.94 Example 1 32 — CH₂CH₂OH OMe 360.99 Example 1 33 racemic

OMe 397.0 Example 1 34 —

OMe 433.1659 Example 1 35 —

OMe 433.1659 Example 3 36 —

OMe 383.1498 Example 3 37 —

OMe Example 3 38 —

OMe 397.1653 Example 3 39 —

OMe 469.1859 Example 3 40 —

OMe 465.1376 Example 3 41 —

OMe 460.1755 Example 3 42 —

OMe 438.1925 Example 3 43 — !! EMBED Chem Draw. OMe 384.1456 Example 344 —

OMe 450.1563 Example 3 45 —

OMe 461.1723 Example 3 46 —

OMe 460.1762 Example 3 47 —

OMe 398.1608 Example 3 48 —

OMe 398.1605 Example 3 49 —

OMe 480.2408 Example 3 50 —

OMe 477.1723 Example 3 51 racemic

OMe 401.0 Example 1 52 racemic

Cl 404.9 Example 1 53 —

Cl 410.9 Example 1 54 Racemic

Cl 418.9 Example 1 55 Racemic

Cl 432.9 Example 1 56 Racemic

464.9 Example 5 57 Racemic

461.9 Example 5 58 — PMB OMe 437.0 Example 1 59 —

Ph 452.9 Example 5 60 —

457.0 Example 5 61 —

442.9 Example 6 62 —

H 377.0 Example 5

The following compounds of FIG. (I) above, wherein R³ is hydrogen and X,Y and Z are CH, are depicted below in Table 2. The Table 2 compoundswere prepared according to the general procedures provided in Examples1-19. The starting materials are either commercially available or may beprepared from commercially available reagents using conventionalreactions well known in the art.

TABLE 2 Exemplary Compounds of FIG. (I), wherein R³ is Hydrogen ExampleStereospecificity R² R¹ MS Method 63 — H

336.97 Example 1  64 Racemic

434.96 Example 1  65 (1S, 2S)

386.1  Example 18 66 (1S, 2S)

386.0  Example 18

The following compounds of FIG. (II) above, wherein R³ is hydrogen, aredepicted below in Table 3. The Table 3 compounds were prepared accordingto the general procedures provided in Examples 1-19. The startingmaterials are either commercially available or may be prepared fromcommercially available reagents using conventional reactions well knownin the art.

TABLE 3 Exemplary compounds of FIG. (II), wherein R³ is Hydrogen ExampleStereospecificity R² R⁷ HRMS Method  67 Racemic

465.9   Example 5  68 (1S, 2S)

466.0   Example 5  69 Racemic

462.9   Example 5  70 Racemic

Cl 419.9   Example 1  71 (1S, 2S)

Cl 420.1496 Example 2  72 racemic

Cl 420.0   Example 2  73 (1S, 2S)

Cl 434.1624 Example 2  74 racemic

451.9   Example 6  75 (1S, 2S)

452.0   Example 6  76 racemic

451.9   Example 6  77 racemic

NMe₂ 429.0   Example 8  78 racemic

Me 400.0   Example 7  79 (1S, 2S)

Me 400.0   Example 7  80 (1S, 2S)

Me 414.2174 Example 7  81 racemic

CN 411.0   Example 7  82 racemic

508.0   Example 5  83 racemic

451.9   Example 5  84 racemic

480.9   Example 5  85 racemic

492.9   Example 5  86 (1S, 2S)

493.0   Example 5  87 racemic

476.9   Example 5  88 racemic

548.0   Example 5  89 (1S, 2S)

481.0   Example 5  90 (1S, 2S)

481.0   Example 5  91 (1S, 2S)

477.0   Example 5  92 (1S, 2S)

464.0   Example 5  93 (1S, 2S)

497.0   Example 5  94 (1S, 2S)

493.0   Example 5  95 (1S, 2S)

477.0   Example 5  96 racemic

469.0   Example 8  97 racemic

486.9   Example 8  98 racemic

471.0   Example 8  99 (1S, 2S)

471.0   Example 8 100 racemic

484.0   Example 8 101 racemic

512.0   Example 8 102 racemic

SMe 431.9   Example 8 103 (1S, 2S)

SMe 432.0   Example 8 104 racemic

SO₂Me 463.9   Example 8 105 racemic

vinyl 412.0   Example 13 106 racemic

Et 414.0   Example 13 107 (1S, 2S)

Et 414.0   Example 13 108 (1S, 2S)

CH₂OH 416.0   Example 15 109 (1S, 2S)

426.0   Example 13 110 (1S, 2S)

428.0   Example 13 111 (1S, 2S)

428.0   Example 14 112 (1S, 2S)

441.0   Example 14 113 racemic

CHO 414.0   Example 14 114 racemic

OMe 415.9   Example 9 115 (1S, 2S)

OMe 416.0   Example 9 116 racemic

H 386.0   Example 1 117 racemic

Cl 433.9   Example 11 118 racemic

Cl 461.9   Example 11 119 (1S, 2S)

Me 442.2128 Example 11 120 racemic

Cl 417.9   Example 10 121 (1S, 2S)

Cl 519.0   Example 12 122 (1S, 2S)

Cl 419.0   Example 12 123 (1S, 2S)

Cl 460.9   Example 12 124 (1S, 2S)

Cl 496.9   Example 12 125 (1S, 2S)

Cl 433.0   Example 12 126 (1S, 2S)

Cl 447.0   Example 12 127 racemic

416.0   Example 16 128 (1S, 2S)

416.1967 Example 17

The following compounds of formula (I) above, wherein X and Y are CH,are depicted below in Table 4. The Table 4 compounds were preparedaccording to the general procedures provided in Examples 1-19. Thestarting materials are either commercially available or may be preparedfrom commercially available reagents using conventional reactions wellknown in the art.

TABLE 4 Exemplary compounds of FIG. (I), wherein X and Y are CH ExampleStereospecificity R² R¹ R³ Z HRMS Method 129 —

OMe SMe CH 457.4 Example 16 130 (1S, 2S)

Cl Me N 433.9 Example 19

The utility of the compounds as M1 receptor positive allostericmodulators may be demonstrated by methodology known in the art,including by the assay described below. The assay is designed to selectcompounds that possess modulator activity at the acetylcholinemuscarinic M1 receptor or other muscarinic receptors expressed in CHOnfat cells by measuring the intracellular calcium with a FLIPR³⁸⁴Fluorometric Imaging Plate Reader System. The assay studies the effectof one or several concentrations of test compounds on basal oracetylcholine-stimulated Ca²⁺ levels using FLIPR.

Compounds are prepared and subjected to a preincubation period of 4 min.Thereafter, a single EC₂₀ concentration of acetylcholine is added toeach well (3 nM final). The intracellular Ca²⁺ level of each sample ismeasured and compared to an acetylcholine control to determine anymodulatory activity.

Cells: CHOnfat/hM1, hM2, hM3 or hM4 cells are plated 24 hr before theassay at a density of 18,000 cells/well (100 μL) in a 384 well plate.CHOnfat/hM1 and CHOnfat/hM3 Growth Medium: 90% DMEM (Hi Glucose): 10% HIFNS; 2mM L-glutamine; 0.1 mM NEAA; Pen-Strep; and 1 mg/ml Geneticin, areadded. For M2Gqi5CHOnfat and M4Gqi5CHOnfat cells, an additional 600ug/ml hygromycin is added.

Equipment: 384 well plate, 120 μL addition plate; 96-well Whatman 2 mlUniplate Incubator, 37° C., 5% CO2; Skatron EMBLA-384 Plate Washer;Multimek Pipetting System; Genesis Freedom 200 System; Mosquito System;Temo Nanolitre Pipetting System; and FLIPR³⁸⁴ Fluorometric Imaging PlateReader System are used.

Buffers. Assay Buffer: Hanks Balanced Salt Solution with 20 mM Hepes,2.5 mM Probenecid (Sigma P-8761) first dissolved in 1 N NaOH, 1% BovineSerum Albumin (Sigma A-9647). Dye Loading Buffer: Assay Buffer plus 1%Fetal Bovine Serum and Fluo-4AM/Pluronic Acid Mixture. 2 mM Fluo-4AMester stock in DMSO (Molecular Probes F-14202) Concentration of 2 μM inbuffer for a final concentration of 1 μM in Assay. 20% Pluronic AcidSolution stock, with concentration of 0.04% in Buffer, 0.02% in Assay.

65 μL of 2 mM Fluo-4AM are mixed with 130 μL of 20% Pluronic Acid. Theresulting solution and 650 μL FBS is added to the assay buffer for atotal volume of 65 mL. Positive Controls: 4-Br-A23187: 10 mM in DMSO;final concentration 10 μM. Acetylcholine: 10 mM in water, working stockat both 20 μM and 30 μM in assay buffer, final concentration of 10 μM.This is used to check the maximum stimulation of the CHOK1/hM1 cells. 20μM (2×) acetylcholine is added in the preincubation part of the assay,and the 30 μM (3×) stock is added in the second part.(EC₂₀)Acetylcholine: 10 mM in water, working stock of 9 nM (3×), andfinal concentration in assay is 3 nM. This is used after thepreincubation with test compounds. Addition of the EC₂₀ Acetylcholine toeach well with a test compound will ascertain any modulator activity. 24wells contain 3 nM Acetylcholine alone as a control.

Determining Activity of Putative Compounds:

Screening Plate: Compounds are titrated in 96-well plates (columns2-11), 100% DMSO, started at a concentration of 15 mM (150× stockconcentration), and 3-fold serial dilutions using Genesis Freedom200System. Four 96-well plates are combined into a 384-well plate usingMosquito Nanolitre Pipetting System by transferring 1 μl of serialdiluted compounds to each well, and 1 mM acetylcholine (100× stockconcentration) were added as a control. Using Temo, 49 μl assay bufferis added to each well of the 384-well plate right before assay.

In a 96-well Whatman 2 ml Uniplate, 9 nM Acetylcholine (3×) is pipettedinto wells corresponding to the screening compounds, and into controlwells. The 30 μM acetylcholine control (3×) is added into control wells,and the 3× agonist plate is transferred into a 384 well plate.

Cells are washed three times with 100 μL of buffer, leaving 30 μL ofbuffer in each well. Using Multimek, 30 μL of Dye Loading Buffer isadded into each well and incubated at 37° C., 5% CO₂ for up to one hr.

After 60 min, the cells are washed three times with 100 μL of buffer,leaving 30 μL of buffer in each well. The cell plate, screening plate,and agonist addition plates are placed on the platform in the FLIPR andthe door closed. A signal test to check background fluorescence andbasal fluorescence signal is performed. Laser intensity is adjusted ifnecessary.

4 min of preincubation with the test compounds is provided to determineany agonist activity on the M1 receptor by comparison to the 1 mMacetylcholine control. After preincubation, the EC₂₀ value ofacetylcholine (3 nM final) is added to determine any modulator activity,

A further description of the muscarinic FLIPR assay can be found inInternational patent application WO2004/073639.

In particular, the compounds of the following examples had activity inthe aforementioned assay, generally with an IP (inflection point) of 10μM (10,000 nM) or less. The inflection point is calculated from theFLIPR values, and is a measure of activity. Such a result is indicativeof the intrinsic activity of the compounds in use as M1 allostericmodulators.

IP values from the aforementioned assay for representative exemplarycompounds of the invention (as described herein) are provided below inTable 1 below:

IP Value Example (nM) 1 51 2 21 3 1800 4 3500 5 8 6 31 7 74 8 93 9 73 101300 11 3600 12 >10000 13 21 14 46 15 24 16 84 17 63 18 228 19 1428

The following abbreviations are used throughout the text;

Me: methyl

Et: ethyl

t-Bu: tert-butyl

Ar: aryl

Ph: phenyl

Bn: benzyl

DCE: dichloroethylene

HMDS: hexamethyldisilaane

DMF: dimethylformamide

DMFDMA: N,N-dimethylformamide dimethylacetal

THF: tetrahydrofuran

BOP: benzotriazolyloxytris (dimethylamino) phosphoniumhexafluorophosphate

Boc: tert-butyloxycarbonyl

TEA: triethylamine

TPAP: teta-n-propyl ammonium perruthenate

NMO: N-methyl morpholine N-oxide

CIZn: Chlorozinc

dppf: diphenylphosphorousferrocenyl

PMB: p-methoxybenzyl

Ms: mesyl

Ac: acetyl

DMSO: dimethylsulfoxide

DCM: dichloromethane

m-CPBA: meta-chloroperoxybenzoic acid

DMEM: Dulbecco's Modified Eagle Medium (High Glucose)

FBS: fetal bovine serum

rt: room temperature

aq: aqueous

HPLC: high performance liquid chromatography

MS: mass spectrometry

While the invention has been described and illustrated with reference tocertain particular embodiments thereof, those skilled in the art willappreciate that various adaptations, changed, modifications,substitutions, deletions, or additions of procedures and protocols maybe made without departing from the spirit and scope of the invention. Itis intended, therefore that the invention be defined by the scope of theclaims that follow and that such claims be interpreted as broadly as isreasonable.

What is claimed is:
 1. A compound of general formula (I):

or a pharmaceutically acceptable salts thereof, wherein X, Y and Z areeach CH and Q is C, or one of X, Y, Q and Z is N and the others are CHor C, or X and Y are CH and Q, R¹ and Z are linked together to form anaphthyl group; R¹ is selected from the group consisting of (1)hydrogen, (2) aryl, (3) a heteroaryl group which is a cyclic orpolycyclic group, having from five to twelve ring atoms, said ring atomsselected from C, O, N or S, at least one of which is O, N or S, (4)halogen, (5) —CN. (6) —O—C₁₋₆alkyl, (7) —C₁₋₆ alkyl, (8) —C₂₋₆ alkenyl(9) —S(═O)_(n)—R⁴, (10) —NR⁵A_(R)5B, wherein said aryl, heteroaryl,alkyl and alkenyl moiety is optionally substituted with one or more (a)halogen, (b) hydroxy, (c) —O—C₁₋₆ alkyl, (d) —C₁₋₆ alkyl, (e)—C(═O)—(O)_(m)—R⁶, (f) —N(R^(5A)R^(5B)), (g) —S(═O)_(n)—R⁸, or (h) oxo,provided that when Q is N then R¹ is absent: R² is selected from thegroup consisting of (1) hydrogen, (2) aryl, (3) a heteroaryl group whichis a cyclic or polycyclic group, having from five to twelve ring atoms,said ring atoms selected from C, O, N or S, at least one of which is O,N or S, (4) a heterocyclic group, which is a non-aromatic cyclic orpolycyclic group having from five to twelve ring atoms selected from C,O, N or S, at least one of which is O, N or S, (5) —O—C₁₋₆ alkyl, (6)—C₁₋₆ alkyl (7) —C₂₋₆ alkenyl, (8) —S(═O)_(n)—R⁴, (9) —C₃₋₈ cycloalkyl,(10) —C₅₋₈ cycloalkenyl, (11) —NR^(5A)R^(5B), wherein said aryl,heteroaryl, heterocyclyl, alkyl, alkenyl, cycloalkyl and cycloalkenylmoiety is optionally substituted with one or more (a) halogen, (b)hydroxy, (c) —O—C₁₋₆ alkyl, (d) —C₁₋₆ alkyl, (e) —S—(═O)_(n)—R⁸, (f)—C₂₋₆ alkenyl, (g) —CN, (h) —C(═O)—(O)_(m)—R⁶, (i) —NR^(5A)R^(5B), (j)oxo, (k) aryl, (l) a heteroaryl group which is a cyclic or polycyclicgroup, having from five to twelve ring atoms, said ring atoms selectedfrom C, O, N or S, at least one of which is O, N or S, (m) aheterocyclic group, which is a non-aromatic cyclic or polycyclic grouphaving from five to twelve ring atoms selected from C, O, N or S, atleast one of which is O, N or S (n) —OC═(O)—R⁶, wherein the alkyl,alkenyl, aryl, heteroaryl or heterocyclic moiety is optionallysubstituted with one or more (i) halogen, (ii) —C₁₋₆ alkyl, or (iii)—OC₁₋₆ alkyl; R³ is selected from the group consisting of (1) hydrogen.(2) —C₁₋₆ alkyl, and (3) —S(O)_(n)—R⁴, wherein said R³ alkyl moiety isoptionally substituted with one or more (a) halogen, (b) cyano, and (c)—O—C₁₋₆ alkyl, wherein said alkyl is optionally substituted with one ormore halo; R⁴, R⁶ and R⁸ are independently selected from the groupconsisting of (1) hydrogen, (2) —C₁₋₆ alkyl, and (3) —(CH₂)_(n)-aryl,wherein said R⁴, R⁶ and R⁸ alkyl or aryl moiety is optionallysubstituted with one or more (a) halogen, (b) cyano, and (c) —O—C₁₋₆alkyl, wherein said alkyl is optionally substituted with one or morehalogen; R^(5A) and R^(5B) are selected from the group consisting of (1)hydrogen, (2) —C₁₋₆ alkyl, (3) —C₃₋₆ cycloalkyl, (4) —C(═O)—O—R⁶, (5)—S(O)₂—R⁶, or R^(5A) and R^(5B) are linked together with the nitrogen towhich they are both attached to form a 2-6 membered carbocyclic ring,wherein one or two of the ring carbon atoms is optionally replaced by anitrogen, oxygen or sulfur; m is 0 or 1; and n is 0,1 or
 2. 2. Acompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein Q is C, X and Y each CH and Z is N.
 3. A compound of claim 1, ora pharmaceutically acceptable salt thereof, wherein X, Y, Z are each CH,and Q is C.
 4. A compound of claim 1, or a pharmaceutically acceptablesalt thereof, wherein X and Z are each CH, Q is C and Y is N.
 5. Acompound of any of claims 1 to 4, or a pharmaceutically acceptable saltthereof, wherein , R¹ is selected from the group consisting of (1)halogen, (2) —CN, (3) —O—C₁₋₆ alkyl, or (4) —C₁₋₆ alkyl, wherein saidalkyl is optionally substituted with one or more (a) halogen, (b)hydroxy, (c) —O—C₁₋₆ alkyl, (d) —C₁₋₆ alkyl, (e) —C(═O)—(O)_(m)—R⁶, (f)—NR^(5A)R^(5B), or (g) oxo.
 6. A compound of any of claims 1 to 4, or apharmaceutically acceptable salt thereof, wherein , R¹ is selected fromthe group consisting of (1)aryl, or (2) heteroaryl, wherein the R¹ arylor heteroaryl moiety is optionally substituted with one or more (a)halogen, (b) hydroxy, (c) —O—C₁₋₆ alkyl (d) —C₁₋₆ alkyl, or (e)—S(O)_(n)—R⁸.
 7. A compound of any of claims 1 to 6, or apharmaceutically acceptable salt thereof, wherein R² is —C₃₋₈cycloalkyl, optionally substituted with one or more (a) hydroxy, (b)—O—C₁₋₆ alkyl, or (c) oxo.
 8. A compound of any of claims 1 to 6, or apharmaceutically acceptable salt thereof, wherein R² is selected fromthe group consisting of (1) aryl, (2) heteroaryl, or (3) —C₁₋₆ alkyl,wherein said aryl, heteroaryl or alkyl is optionally substituted withone or more (a) halogen, (b) hydroxy, (c) —O—C₁₋₆ alkyl, (d) —C₁₋₆alkyl, (e) —CN, (f) —C(═O)—(O)_(m)—R⁶, (g) —NR^(5A)R^(5B), (h) oxo, (i)aryl, and (j) heteroaryl.
 9. A compound of claim 1 or a pharmaceuticallyacceptable salt thereof, wherein R³ is hydrogen.
 10. A compound of claim1, or a pharmaceutically acceptable salt thereof, which is selected fromthe group consisting ofrac-3-[trans-2-hydroxyclohexyl]-6-[(6-methylpyridin-3-yl)methyl]benzo[h]quinazolin-4(3H)-one;3-[(1S,2S)-2-hydroxycyclohexyl]-6-[(6-methylpyridin-3-yl)methyl]benzo[h]quinazolin-4(3H)-one;6-(4-methoxybenzyl)-3-(5-methyl)-1H-pyrazol-3-yl)benzo[h]quinazolin-4(3H)-one;6-(4-methoxybenzyl)-3-pyridin-3-ylbenzo[h]quinazolin-4(3H)-one;rac-3-[trans-2-hydroxycyclohexyl]-6-{[6-(1-methyl-1H-pyrazol-4-yl)pyridine-3-yl]methyl}benzo[h]quinazolin-4(3H)-one;rac-3-[trans-2-hydroxycyclohexyl]-6-{[6-(1H-pyrazol-1-yl)pyridine-3-yl]methyl}benzo[h]quinazolin-4(3H)-one;rac-5-({3-[trans-2-hydroxycyclohexyl]-4-oxo-3,4-dihydrobenzo[h]quinazolin-6-yl}methyl)pyridine-2-carbonitrile;rac-3-[trans-2-hydroxycyclohexyl]-6-{[6-methylfulfonyl)pyridine-3-yl]methyl}benzo[h]quinazolin-4(3H)-one;rac-3-[trans-2-hydroxycyclohexyl]-6-[6-methoxypyridine-3-yl)methyl]benzo[h]quinazolin-4(3H)-one;6-[(6-chloropyridin-3-yl)methyl]-3-(2-oxycyclohexy)benzo[h]quinazolin-4(3H)-one;trans-2-[6-[(6-chloropyridin-3-yl)methyl]-4-oxobenzo[h]quinazolin-3(4H)-yl]cyclohexylrac-acetate;N-{(1S,2S)-2-[6-[(6-chloropyridin-3-yl)methyl]-4-oxobenzo[h]quinazolin-3(4H)-yl]cyclohexyl}acetamide;3-[(1S,2S)-2-hydroxycyclohexyl]-6-[(6-isopropylpyridin-3-yl)methylbenzo[h]quinazolin-4(3H)-one3-[(1S,2S)-2-hydroxycyclohexyl]-6-{[(6-(1-hydroxy-1-methylethyl)pyridin-3-yl]methyl}benzo[h]quinazolin-4(3H)-one;rac-3-[trans-2-hydroxycyclohexyl]-6-{[(6-hydroxymethyl)pyridin-3-yl]methyl}benzo[h]quinazolin-4(3H)-one;rac-3-[trans-2-hydroxycyclohexyl]-6-[(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]benzo[h]quinazolin-4(3H)-one;3-[(1S,2S)-2-hydroxycyclohexyl]-6-[(6-methyl-1-oxidopyridin-3-yl)methyl]benzo[h]quinazolin-4(3H)-one;3-[(1S,2S)-2-hydroxycyclohexyl]-6-(pyridin-2-ylmethyl)benzo[h]quinazolin-4(3H)-one;6-[(6-chloropyridin-3-yl)methyl]-3-[(1S,2S)-2-hydroxycyclohexyl]-2-methylbenzo[h]quinazolin-4(3H)-one;or a pharmaceutically acceptable salt thereof.
 11. A compound of claim1, or a pharmaceutically acceptable salt thereof, which is selected fromthe group consisting ofrac-3-[trans-2-hydroxyclohexyl]-6-[(6-methylpyridin-3-yl)methyl]benzo[h]quinazolin-4(3H)-one;3-[(1S,2S)-2-hydroxycyclohexyl]-6-[(6-methylpyridin-3-yl)methyl]benzo[h]quinazolin-4(3H)-one;6-(4-methoxybenzyl)-3-(5-methyl)-1H-pyrazol-3-yl)benzo[h]quinazolin-4(3H)-one;6-(4-methoxybenzyl)-3-pyridin-3-ylbenzo[h]quinazolin-4(3H)-one;rac-3-[trans-2-hydroxycyclohexyl]-6-{[6-(1-methyl-1H-pyrazol-4-yl)pyridine-3-yl]methyl}benzo[h]quinazolin-4(3H)-one;rac-3-[trans-2-hydroxycyclohexyl]-6-{[6-(1H-pyrazol-1-yl)pyridine-3-yl]methyl}benzo[h]quinazolin-4(3H)-one;rac-5-({3-[trans-2-hydroxycyclohexyl]-4-oxo-3,4-dihydrobenzo[h]quinazolin-6-yl}methyl)pyridine-2-carbonitrile;or a pharmaceutically acceptable salt thereof.
 12. A compound of claim1, wherein X and Y are CH, Q is C, and R¹, R², R³, and Z are depictedbelow: R² R¹ R³ Z

OCH₃ SCH₃ CH

Cl CH₃ N (1S, 2S)


13. A compound of claim 1, wherein the compound of formula (I) is acompound of formula (II):

or a pharmaceutically acceptable salt thereof, wherein R⁷ is selectedfrom the group consisting of (1) hydrogen, (2) aryl, (3) heteroaryl, (4)halogen, (5) —CN, (6) —O—C₁₋₆ alkyl, (7) —C₁₋₆ alkyl, (8) —C₂₋₆ alkenyl(9) —S(═O)_(n)—R⁴, and wherein said, aryl, heteroaryl, alkyl and alkenylmoiety is optionally substituted with one or more (a) halogen, (b)hydroxy, (c) —O—C₁₋₆ alkyl, (d) —C₁₋₆ alkyl, (e) —C(═O)—(O)_(m)—R⁶, (f)—NR^(5A)R^(5B), (g) —S(═O)_(n)—R⁸, and (h) oxo.
 14. A compound of claim13, or a pharmaceutical acceptable salt thereof, wherein R³ is hydrogenand R² and R⁷ are paired as depicted below: Stereospecificity R² R⁷Racemic

(1S, 2S)

Racemic

Racemic

Cl (1S, 2S)

Cl Racemic

Cl (1S, 2S)

Cl racemic

(1S, 2S)

racemic

racemic

N(CH₃)₂ racemic

CH₃ (1S, 2S)

CH₃ (1S, 2S)

CH₃ racemic

CN racemic

racemic

racemic

racemic

(1S, 2S)

racemic

racemic

(1S, 2S)

(1S, 2S)

(1S, 2S)

(1S, 2S)

(1S, 2S)

(1S, 2S)

(1S, 2S)

racemic

racemic

racemic

(1S, 2S)

racemic

racemic

racemic

SCH₃ (1S, 2S)

SCH₃ racemic

SO₂CH₃ racemic

CH₂═CH— racemic

CH₂CH₃ (1S, 2S)

CH₂CH₃ (1S, 2S)

CH₂OH (1S, 2S)

(1S, 2S)

(1S, 2S)

(1S, 2S)

racemic

CHO racemic

OCH₃ (1S, 2S)

OCH₃ racemic

H racemic

Cl racemic

Cl (1S, 2S)

CH₃ racemic

Cl (1S, 2S)

Cl (1S, 2S)

Cl (1S, 2S)

Cl (1S, 2S)

Cl (1S, 2S)

Cl (1S, 2S)

Cl racemic

(1S, 2S)


15. A compound of claim 1, wherein the compound of formula (I) is acompound of formula (III):

or a pharmaceutically acceptable salt thereof, wherein R² and R³ are asdescribed above, and R⁷ is selected from the group consisting of (1)hydrogen, (2) aryl, (3) heteroaryl, (4) halogen, (5) —CN, (6) —O—C₁₋₆alkyl, (7) —C₁₋₆ alkyl, (8) —C₂₋₆ alkenyl (9) —S(═O)_(n)—R⁴, and whereinsaid, aryl, heteroaryl, alkyl and alkenyl moiety is optionallysubstituted with one or more (a) halogen, (b) hydroxy, (c) —O—C₁₋₆alkyl, (d) —C₁₋₆ alkyl, (e) —C(═O)—(O)_(m)—R⁶, (f) —NR^(5A)R^(5B), (g)—S(═O)_(n)—R⁸, and (h) oxo.
 16. A confound of claim 15, wherein R³ ishydrogen, and R² and R⁷ are paired from the group consisting of R² R⁷

OCH₃ H OCH₃ Allyl OCH₃ Me OCH₃ Ph OCH₃

OCH₃ (racemic) 3-pyridyl OCH₃ 4-pyridyl OCH₃

OCH₃

OCH₃ CH₂CH₂CN OCH₃

OCH₃ CH₂CH₂OH OCH₃

OCH₃ (racemic)

OCH₃

OCH₃

OCH₃

OCH₃

OCH₃

OCH₃

OCH₃

OCH₃

OCH₃

OCH₃

OCH₃

OCH₃

OCH₃

OCH₃

OCH₃

OCH₃

OCH₃

OCH₃ (racemic)

Cl (racemic)

Cl

Cl (racemic)

Cl (racemic)

(racemic)

(racemic) PMB OCH₃

H

or a pharmaceutically acceptable salt thereof.
 17. A compound of claim1, wherein the compound of formula (I) is a compound of formula (IV):

or a pharmaceutically acceptable salt thereof, wherein X, Y, Z, R¹ andR³ are as defined in claim
 1. 18. A compound of claim 17, wherein thecompound of formula (IV) is a compound of (IVA)

wherein the bonds between the benzoquinazoline nitrogen and the 1-carbonon the cyclohexyl ring, and the bond between the hydroxy and the2-carbon on the cyclohexyl ring, are trans.
 19. A compound of claim 17or 18, wherein X and Y are each CH and Z is N.
 20. A compound of claim18 or 19, wherein X, Y and Z are each CH.
 21. A compound of formula (V),

wherein R² and Q′ are paired as below: R² Q′ H

(racemic)

(1S, 2S)

(1S, 2S)

or a pharmaceutically acceptable salt thereof.
 22. A pharmaceuticalcomposition comprising a therapeutically effective amount of a compoundof any of claims 1-21, or a pharmaceutically acceptable salt thereof,and a pharmaceutically acceptable carrier.
 23. A pharmaceuticalcomposition for the treatment of a disease or disorder mediated by themuscarinic M1 receptor, wherein said disease or disorder is selectedfrom the group consisting of Alzheimer's disease, schizophrenia, pain orsleep disorders, comprising a therapeutically effective amount of acompound of any of claims 1-21, or a pharmaceutically acceptable saltthereof, and a pharmaceutically acceptable carrier.
 24. Use of apharmaceutical composition of any of claims 1-21 for the treatment of adisease or disorder mediated by the muscarinic M1 receptor, wherein saiddisease or disorder is selected from the group consisting of Alzheimer'sdisease, schizophrenia, pain or sleep disorders.
 25. Use of a compoundof any of claims 1-21, or a pharmaceutically acceptable salt thereof,and a pharmaceutically acceptable carrier, for the manufacture of amedicament for the treatment of a disease or disorder mediated by themuscarinic M1 receptor, wherein said disease or disorder is selectedfrom the group consisting of Alzheimer's disease, schizophrenia, pain orsleep disorders.
 26. A method of treating a disease or disorder mediatedby the muscarinic M1receptor, wherein said disease or disorder isselected from the group consisting of Alzheimer's disease,schizophrenia, pain or sleep disorders in a patient in need thereof,comprising administering to the patient a therapeutically effectiveamount of a compound of any of claims 1-21, or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable carrier.